@article{MTMT:34502176,
	title = {TRPM2 - an adjustable thermostat},
	url = {https://m2.mtmt.hu/api/publication/34502176},
	author = {Bartók, Ádám and Csanády, László},
	doi = {10.1016/j.ceca.2024.102850},
	journal-iso = {CELL CALCIUM},
	journal = {CELL CALCIUM},
	volume = {118},
	unique-id = {34502176},
	issn = {0143-4160},
	year = {2024},
	eissn = {1532-1991},
	orcid-numbers = {Bartók, Ádám/0000-0002-1232-5246; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:34593414,
	title = {Identification of Ligands for Ion Channels: TRPM2},
	url = {https://m2.mtmt.hu/api/publication/34593414},
	author = {Gu, Yushu and Liu, Miaomiao and Ma, Linlin and Quinn, Ronald J.},
	doi = {10.1002/cbic.202300790},
	journal-iso = {CHEMBIOCHEM},
	journal = {CHEMBIOCHEM},
	unique-id = {34593414},
	issn = {1439-4227},
	abstract = {Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, nonselective cation channel with a widespread distribution throughout the body. It is involved in many pathological and physiological processes, making it a potential therapeutic target for various diseases, including Alzheimer's disease, Parkinson's disease, and cancers. New analytical techniques are beneficial for gaining a deeper understanding of its involvement in disease pathogenesis and for advancing the drug discovery for TRPM2-related diseases. In this work, we present the application of collision-induced affinity selection mass spectrometry (CIAS-MS) for the direct identification of ligands binding to TRPM2. CIAS-MS circumvents the need for high mass detection typically associated with mass spectrometry of large membrane proteins. Instead, it focuses on the detection of small molecules dissociated from the ligand-protein-detergent complexes. This affinity selection approach consolidates all affinity selection steps within the mass spectrometer, resulting in a streamlined process. We showed the direct identification of a known TRPM2 ligand dissociated from the protein-ligand complex. We demonstrated that CIAS-MS can identify binding ligands from complex mixtures of compounds and screened a compound library against TRPM2. We investigated the impact of voltage increments and ligand concentrations on the dissociation behavior of the binding ligand, revealing a dose-dependent relationship.Collision-induced affinity selection mass spectrometry (CIAS-MS) can be utilized to directly identify ligands binding to the ion channel TRPM2. CIAS-MS circumvents the need for high mass detection typically associated with mass spectrometry of large membrane proteins. Instead, it focuses on the detection of small molecules dissociated from the ligand-protein-detergent complexes, with all affinity selection steps conducted inside the mass spectrometer. image},
	keywords = {ION CHANNELS; TRPM2; Protein-ligand complex; CIAS-MS; collisional induced activation},
	year = {2024},
	eissn = {1439-7633},
	orcid-numbers = {Ma, Linlin/0000-0002-4716-5158}
}

@article{MTMT:34593412,
	title = {2′-deoxy-ADPR activates human TRPM2 faster than ADPR and thereby induces higher currents at physiological Ca<SUP>2+</SUP> concentrations},
	url = {https://m2.mtmt.hu/api/publication/34593412},
	author = {Pick, Jelena and Sander, Simon and Etzold, Stefanie and Rosche, Anette and Tidow, Henning and Guse, Andreas H. and Fliegert, Ralf},
	doi = {10.3389/fimmu.2024.1294357},
	journal-iso = {FRONT IMMUNOL},
	journal = {FRONTIERS IN IMMUNOLOGY},
	volume = {15},
	unique-id = {34593412},
	issn = {1664-3224},
	abstract = {TRPM2 is a Ca2+ permeable, non-selective cation channel in the plasma membrane that is involved in the innate immune response regulating, for example, chemotaxis in neutrophils and cytokine secretion in monocytes and macrophages. The intracellular adenine nucleotides ADP-ribose (ADPR) and 2 '-deoxy-ADPR (2dADPR) activate the channel, in combination with their co-agonist Ca2+. Interestingly, activation of human TRPM2 (hsTRPM2) by 2dADPR is much more effective than activation by ADPR. However, the underlying mechanism of the nucleotides' differential effect on the channel is not yet fully understood. In this study, we performed whole-cell patch clamp experiments with HEK293 cells heterologously expressing hsTRPM2. We show that 2dADPR has an approx. 4-fold higher Ca2+ sensitivity than ADPR (EC50 = 190 and 690 nM). This allows 2dADPR to activate the channel at lower and thus physiological intracellular Ca2+ concentrations. Kinetic analysis of our data reveals that activation by 2dADPR is faster than activation by ADPR. Mutation in a calmodulin binding N-terminal IQ-like motif in hsTRPM2 completely abrogated channel activation by both agonists. However, mutation of a single amino acid residue (W1355A) in the C-terminus of hsTRPM2, at a site of extensive inter-domain interaction, resulted in slower activation by 2dADPR and neutralized the difference in rate of activation between the two agonists. Taken together, we propose a mechanism by which 2dADPR induces higher hsTRPM2 currents than ADPR by means of faster channel activation. The finding that 2dADPR has a higher Ca2+ sensitivity than ADPR may indicate that 2dADPR rather than ADPR activates hsTRPM2 in physiological contexts such as the innate immune response.},
	keywords = {CALMODULIN; Calcium Signaling; TRPM2; ADPR; calcium sensitivity; 2 '-deoxy-ADPR},
	year = {2024},
	eissn = {1664-3224},
	orcid-numbers = {Pick, Jelena/0000-0002-9281-1155}
}

@article{MTMT:34720489,
	title = {Reviewing critical TRPM2 variants through a structure-function lens},
	url = {https://m2.mtmt.hu/api/publication/34720489},
	author = {Tóth, Ádám Viktor and Bartók, Ádám},
	doi = {10.1016/j.jbiotec.2024.02.017},
	journal-iso = {J BIOTECHNOL},
	journal = {JOURNAL OF BIOTECHNOLOGY},
	volume = {385},
	unique-id = {34720489},
	issn = {0168-1656},
	year = {2024},
	eissn = {1873-4863},
	pages = {49-57},
	orcid-numbers = {Bartók, Ádám/0000-0002-1232-5246}
}

@article{MTMT:34252725,
	title = {TRPM channels in health and disease},
	url = {https://m2.mtmt.hu/api/publication/34252725},
	author = {Chubanov, Vladimir and Koettgen, Michael and Touyz, Rhian M. and Gudermann, Thomas},
	doi = {10.1038/s41581-023-00777-y},
	journal-iso = {NAT REV NEPHROL},
	journal = {NATURE REVIEWS NEPHROLOGY},
	unique-id = {34252725},
	issn = {1759-5061},
	abstract = {Different cell channels and transporters tightly regulate cytoplasmic levels and the intraorganelle distribution of cations. Perturbations in these processes lead to human diseases that are frequently associated with kidney impairment. The family of melastatin-related transient receptor potential (TRPM) channels, which has eight members in mammals (TRPM1-TRPM8), includes ion channels that are highly permeable to divalent cations, such as Ca2+, Mg2+ and Zn2+ (TRPM1, TRPM3, TRPM6 and TRPM7), non-selective cation channels (TRPM2 and TRPM8) and monovalent cation-selective channels (TRPM4 and TRPM5). Three family members contain an enzymatic protein moiety: TRPM6 and TRPM7 are fused to alpha-kinase domains, whereas TRPM2 is linked to an ADP-ribose-binding NUDT9 homology domain. TRPM channels also function as crucial cellular sensors involved in many physiological processes, including mineral homeostasis, blood pressure, cardiac rhythm and immunity, as well as photoreception, taste reception and thermoreception. TRPM channels are abundantly expressed in the kidney. Mutations in TRPM genes cause several inherited human diseases, and preclinical studies in animal models of human disease have highlighted TRPM channels as promising new therapeutic targets. Here, we provide an overview of this rapidly evolving research area and delineate the emerging role of TRPM channels in kidney pathophysiology.},
	year = {2023},
	eissn = {1759-507X},
	orcid-numbers = {Chubanov, Vladimir/0000-0002-6042-4193}
}

@article{MTMT:33687612,
	title = {On the modulation of TRPM channels: Current perspectives and anticancer therapeutic implications},
	url = {https://m2.mtmt.hu/api/publication/33687612},
	author = {Ciaglia, T. and Vestuto, V. and Bertamino, A. and González-Muñiz, R. and Gómez-Monterrey, I.},
	doi = {10.3389/fonc.2022.1065935},
	journal-iso = {FRONT ONCOL},
	journal = {FRONTIERS IN ONCOLOGY},
	volume = {12},
	unique-id = {33687612},
	issn = {2234-943X},
	abstract = {The transient melastatin receptor potential (TRPM) ion channel subfamily functions as cellular sensors and transducers of critical biological signal pathways by regulating ion homeostasis. Some members of TRPM have been cloned from cancerous tissues, and their abnormal expressions in various solid malignancies have been correlated with cancer cell growth, survival, or death. Recent evidence also highlights the mechanisms underlying the role of TRPMs in tumor epithelial-mesenchymal transition (EMT), autophagy, and cancer metabolic reprogramming. These implications support TRPM channels as potential molecular targets and their modulation as an innovative therapeutic approach against cancer. Here, we discuss the general characteristics of the different TRPMs, focusing on current knowledge about the connection between TRPM channels and critical features of cancer. We also cover TRPM modulators used as pharmaceutical tools in biological trials and an indication of the only clinical trial with a TRPM modulator about cancer. To conclude, the authors describe the prospects for TRPM channels in oncology. Copyright © 2023 Ciaglia, Vestuto, Bertamino, González-Muñiz and Gómez-Monterrey.},
	keywords = {CANCER; cell proliferation; Autophagy; MODULATORS; TRPM channels},
	year = {2023},
	eissn = {2234-943X}
}

@article{MTMT:34323601,
	title = {Modulation and Regulation of Canonical Transient Receptor Potential 3 (TRPC3) Channels},
	url = {https://m2.mtmt.hu/api/publication/34323601},
	author = {Cole, Bethan A. and Becker, Esther B. E.},
	doi = {10.3390/cells12182215},
	journal-iso = {CELLS-BASEL},
	journal = {CELLS},
	volume = {12},
	unique-id = {34323601},
	abstract = {Canonical transient receptor potential 3 (TRPC3) channel is a non-selective cation permeable channel that plays an essential role in calcium signalling. TRPC3 is highly expressed in the brain and also found in endocrine tissues and smooth muscle cells. The channel is activated directly by binding of diacylglycerol downstream of G-protein coupled receptor activation. In addition, TRPC3 is regulated by endogenous factors including Ca2+ ions, other endogenous lipids, and interacting proteins. The molecular and structural mechanisms underlying activation and regulation of TRPC3 are incompletely understood. Recently, several high-resolution cryogenic electron microscopy structures of TRPC3 and the closely related channel TRPC6 have been resolved in different functional states and in the presence of modulators, coupled with mutagenesis studies and electrophysiological characterisation. Here, we review the recent literature which has advanced our understanding of the complex mechanisms underlying modulation of TRPC3 by both endogenous and exogenous factors. TRPC3 plays an important role in Ca2+ homeostasis and entry into cells throughout the body, and both pathological variants and downstream dysregulation of TRPC3 channels have been associated with a number of diseases. As such, TRPC3 may be a valuable therapeutic target, and understanding its regulatory mechanisms will aid future development of pharmacological modulators of the channel.},
	keywords = {TRP channel; ion channel pharmacology; TRPC3 gating},
	year = {2023},
	eissn = {2073-4409}
}

@article{MTMT:34171052,
	title = {Advances in the structural mechanism of TRPC channels},
	url = {https://m2.mtmt.hu/api/publication/34171052},
	author = {Guo, W. and Chen, L.},
	doi = {10.1360/TB-2023-0029},
	journal-iso = {KEXUE TONGBAO / CHINESE SCIENCE BULLETIN},
	journal = {KEXUE TONGBAO / CHINESE SCIENCE BULLETIN},
	volume = {68},
	unique-id = {34171052},
	issn = {0023-074X},
	abstract = {Transient receptor potential canonical channels (TRPCs) are calcium-permeable, nonselective cation channels. Human TRPC channels contain six functional members: TRPC1, and TRPC3-7, and they are widely distributed in many tissues. These channels are involved in numerous physiological processes, including regulating myogenic tone and blood pressure, endothelial barrier function regulation, hypoxic pulmonary vasoconstriction, neuronal function, and kidney function. They are also associated with several diseases, including traumatic brain injury, pathologic cardiac hypertrophy, atherosclerosis, the development of cancer, and diabetes. Specifically, gain-of-function mutations of the TRPC6 gene in humans cause focal segmental glomerular sclerosis (FSGS), a chronic kidney disease for which there is no effective treatment. Consequently, TRPC channels serve as drug targets for several diseases, including FSGS and anxiety. Recent developments in single-particle cryo-EM permit the determination of the structures of multiple TRPC channel members (TRPC3, TRPC4, TRPC5, and TRPC6) in multiple states at near-atomic resolutions. These structures demonstrate that TRPC channels are tetramers composed of two layers: The upper transmembrane domain (TMD) and the lower intracellular domain (ICD). The ICD layer consists of ankyrin repeat domains (ARD), linker helices domains (LHD), the TRP helix, and C terminal helices. The four protomers’ voltage sensor-like domains (VSLD) and pore domains form the TMD layer. ICD has a bell-like shape with a large central chamber and caps below TMD. The structures reveal both the inhibitory calcium binding site in ICD and the activating calcium binding site in TMD. Calcium binding to the inhibitory site results in the closure of the ICD and the restriction of ion flow through the ICD, whereas calcium dissociation from the inhibitory site results in the opening of the ICD and the unrestricted flow of ions through the ICD. Calcium binding to the activating site increases its activity. Additionally, the binding pockets and binding poses of several small molecule modulators of TRPC channels are identified. Their binding sites are distributed across three distinct regions of TMD. One of the pockets partially overlaps the endogenous activating lipid diacylglycerol-binding site, while another partially overlaps the activating calcium-binding site. In conclusion, these structural findings combined with functional analysis, particularly site-directed mutagenesis data, reveal how intracellular calcium concentrations bi-directionally modulate the TRPC channel, how small molecules bind and tune the activity of TRPC channels, and how the gain-of-function mutations found in FSGS patients over-activate the intracellular calcium signaling of kidney podocytes via the TRPC6 channel in a positive feedback manner. These developments lay the groundwork for a more in-depth mechanistic dissection of TRPC channels. They would also facilitate the discovery of drugs that target TRPC channels to treat associated diseases. © 2023 Chinese Academy of Sciences. All rights reserved.},
	keywords = {Brain; Blood Pressure; calcium; BINDING-SITES; BINDING SITES; pathology; DISEASES; chronic kidney disease; chronic kidney disease; Chemical activation; Activation analysis; calcium binding; TRANSMEMBRANE DOMAIN; cryo-EM; cryo-EM; intracellular domain; Trans-membrane domains; Transient receptor potential canonical channel; Transient receptor potentials; focal segmental glomerular sclerosis (FSGS); transient receptor potential canonical channel (TRPC); Focal segmental glomerular sclerose},
	year = {2023},
	pages = {2213-2220}
}

@article{MTMT:34171044,
	title = {Identification of TRPM2 as a prognostic factor correlated with immune infiltration in ovarian cancer},
	url = {https://m2.mtmt.hu/api/publication/34171044},
	author = {Huang, W. and Wu, Y. and Luo, N. and Shuai, X. and Guo, J. and Wang, C. and Yang, F. and Liu, L. and Liu, S. and Cheng, Z.},
	doi = {10.1186/s13048-023-01225-y},
	journal-iso = {J OVARIAN RES},
	journal = {JOURNAL OF OVARIAN RESEARCH},
	volume = {16},
	unique-id = {34171044},
	issn = {1757-2215},
	abstract = {Introduction: Ovarian cancer (OC) is one of the most common gynecologic malignant cancers with the current survival rate remaining low. TRPM2 has been reported as a survival predictor in various cancers but not in OC. The aim of this study is to explore the role and its underlying mechanism of TRPM2 in OC. Methods: The transcriptome data and clinical data were obtained from TCGA, GTEx, and GEO (GSE17260). DriverDBv3 and PrognoScan were used to analyze survival correlations. GSEA analysis was performed to uncover the underlying mechanism. The correlations between TRPM2 and immune score, immune cell infiltration were analyzed by TIMER2.0. Results: TRPM2 was highly expressed in OC and high TRPM2 expression was related to the poor prognosis based on the Kaplan-Meier curves, univariate and multivariate analysis. The enrichment analysis suggested that TRPM2 was involved in immune-related pathways. Positive correlations were also observed between TRPM2 expression and immune score and immune cells covering B cells, T cells, macrophage, neutrophil, and myeloid dendritic cells. We also found that TRPM2 was positively related to immune checkpoints including ICOSLG, CD40, CD86, etc. TRPM2 expression had a positive correlation with M2 macrophage, but not with M1 macrophage. Besides, TRPM2 showed a strong positive correlation with pyroptosis-related genes including NLRP3, NLRC4, NOD2, NOD1, IL1B, GSDMD. Conclusion: Our study demonstrated that TRPM2 is a poor prognostic prediction factor in ovarian cancer and is correlated to the immune microenvironment and pyroptosis. TRPM2 may act as a new immunotherapy target, which promoted the survival rate of OC patients. © 2023, BioMed Central Ltd., part of Springer Nature.},
	keywords = {Female; Female; Humans; GENETICS; ARTICLE; B-LYMPHOCYTES; immunology; human; Prognosis; Prognosis; Prognosis; MACROPHAGE; neutrophil; correlation analysis; caspase recruitment domain protein 15; controlled study; cell infiltration; Multivariate Analysis; human cell; protein expression; immunocompetent cell; b lymphocyte; human tissue; T lymphocyte; ovary cancer; cancer patient; cancer survival; transcriptomics; interleukin 1beta; cancer immunotherapy; univariate analysis; CD86 antigen; CD40 antigen; Kaplan Meier method; Ovarian Neoplasms; ovary tumor; Genital Neoplasms, Female; female genital tract tumor; predictor variable; Tumor microenvironment; Tumor microenvironment; caspase recruitment domain protein 4; cryopyrin; myeloid dendritic cell; cancer prognosis; Pyroptosis; Pyroptosis; prognostic assessment; clusterin; transient receptor potential channel M; nucleotide binding oligomerization domain like receptor; Gasdermin; TRPM Cation Channels; Gene set enrichment analysis; TRPM2; TCGA; Immune signaling; PAN-CANCER; M2 macrophage; M1 macrophage; TRPM2 protein, human; inducible T cell costimulator ligand},
	year = {2023},
	eissn = {1757-2215}
}

@{MTMT:34171050,
	title = {Enzymatic and endogenous synthesis of NAD(P)-derived calcium-mobilizing messengers},
	url = {https://m2.mtmt.hu/api/publication/34171050},
	author = {Lee, H.C. and Zhao, Y.J.},
	booktitle = {Nucleic Acids in Medicinal Chemistry and Chemical Biology: Drug Development and Clinical Applications},
	doi = {10.1002/9781119692799.ch3},
	unique-id = {34171050},
	abstract = {Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two structural distinct messengers for mobilizing, respectively, the endoplasmic (ER) and endo-lysosomal Ca2+ stores. They were discovered soon after inositol trisphosphate (IP3 ) but were nucleotides totally unrelated to IP3. As both were hitherto unknown molecules, no information about their enzymatic synthesis had ever been described. The first enzyme shown to be able to cyclize NAD and produce cADPR was the Aplysia ADP-ribosyl cyclase. Sequence comparison identified CD38 as a homolog, which had since been established as the main enzyme for metabolizing cADPR in mammalian cells. Both enzymes have now been shown to be multifunctional, capable of producing not only cADPR but NAADP as well. Their catalytic mechanisms have now been fully elucidated using crystallography and mutagenesis. In contrast, the endogenous biogenesis and regulation of cADPR and NAADP in cells are much less understood. Two recent breakthroughs promise to advance our understanding. The first discovery was the natural existence of two topological forms of CD38. The type II form is dominant on cell surface with its catalytic domain facing outside, while the topologically opposite type III form is expressed mostly in the ER. With its catalytic domain facing the cytosol, type III CD38 is efficient in producing cellular cADPR. The natural existence of type III CD38 has been demonstrated and investigations have now begun to uncover the regulatory mechanisms of its activity, folding, and degradation. Recent studies have also shown that the surface Type II CD38 contributes minimally to cellular cADPR but may be responsible to produce NAADP after it is internalized by endocytosis into the acidic endo-lysosomes. The second surprising finding is SARM1, a regulator of axonal degeneration and a protein without any sequence similarity with CD38 but can catalyze the same multi-reactions to produce cADPR and NAADP. It is an autoregulated enzyme and its cADPR-producing activity is activated by nicotinamide mononucleotide. Another metabolite of NAD, ADP-ribose, that is also produced by CD38 and SARM1, has signaling activity in gating the Ca2+ -permeable TRPM2 channel. Whether it acts as a Ca2+ -messenger under physiological conditions, however, remained to be established. With these advances, the messenger functions of these metabolites derived from NAD(P) have entered a new territory. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc. All rights reserved.},
	keywords = {calcium; ADP-ribosyl Cyclase; NAADP; ADPR; CD38; SARM1; cADPR; RPM2},
	year = {2023},
	pages = {84-112}
}

@article{MTMT:34125124,
	title = {TRPM2: bridging calcium and ROS signaling pathways—implications for human diseases},
	url = {https://m2.mtmt.hu/api/publication/34125124},
	author = {Maliougina, M. and El, Hiani Y.},
	doi = {10.3389/fphys.2023.1217828},
	journal-iso = {FRONT PHYSIOL},
	journal = {FRONTIERS IN PHYSIOLOGY},
	volume = {14},
	unique-id = {34125124},
	abstract = {TRPM2 is a versatile and essential signaling molecule that plays diverse roles in Ca2+ homeostasis and oxidative stress signaling, with implications in various diseases. Research evidence has shown that TRPM2 is a promising therapeutic target. However, the decision of whether to activate or inhibit TRPM2 function depends on the context and specific disease. A deeper understanding of the molecular mechanisms governing TRPM2 activation and regulation could pave the way for the development of innovative therapeutics targeting TRPM2 to treat a broad range of diseases. In this review, we examine the structural and biophysical details of TRPM2, its involvement in neurological and cardiovascular diseases, and its role in inflammation and immune system function. In addition, we provide a comprehensive overview of the current knowledge of TRPM2 signaling pathways in cancer, including its functions in bioenergetics, oxidant defense, autophagy, and response to anticancer drugs. Copyright © 2023 Maliougina and El Hiani.},
	keywords = {Inflammation; calcium; review; human; drug response; Nerve Degeneration; nonhuman; disease course; Aging; PACLITAXEL; Calcium ion; immune system; glutamic acid; PROTEIN FUNCTION; Drug targeting; Cancer chemotherapy; docetaxel; doxorubicin; reactive oxygen metabolite; NEUROBLASTOMA; ischemic stroke; FLUOROURACIL; bacterial infection; breast cancer; cisplatin; cancer growth; Biophysics; tamoxifen; protein structure; Calcium Signaling; Autophagy; Acute myeloid leukemia; Bioenergy; stomach cancer; glioblastoma; colon cancer; calcium homeostasis; Bioenergetics; channel gating; myocardial ischemia reperfusion injury; transient receptor potential channel M2; Calcium signal; autophagy (cellular); Oxidative stress; Oxidative stress; oxidant defense; TRPM2 cation channels},
	year = {2023},
	eissn = {1664-042X}
}

@article{MTMT:34171048,
	title = {Structural mechanisms of TRPM7 activation and inhibition},
	url = {https://m2.mtmt.hu/api/publication/34171048},
	author = {Nadezhdin, K.D. and Correia, L. and Narangoda, C. and Patel, D.S. and Neuberger, A. and Gudermann, T. and Kurnikova, M.G. and Chubanov, V. and Sobolevsky, A.I.},
	doi = {10.1038/s41467-023-38362-3},
	journal-iso = {NAT COMMUN},
	journal = {NATURE COMMUNICATIONS},
	volume = {14},
	unique-id = {34171048},
	issn = {2041-1723},
	abstract = {The transient receptor potential channel TRPM7 is a master regulator of the organismal balance of divalent cations that plays an essential role in embryonic development, immune responses, cell mobility, proliferation, and differentiation. TRPM7 is implicated in neuronal and cardiovascular disorders, tumor progression and has emerged as a new drug target. Here we use cryo-EM, functional analysis, and molecular dynamics simulations to uncover two distinct structural mechanisms of TRPM7 activation by a gain-of-function mutation and by the agonist naltriben, which show different conformational dynamics and domain involvement. We identify a binding site for highly potent and selective inhibitors and show that they act by stabilizing the TRPM7 closed state. The discovered structural mechanisms provide foundations for understanding the molecular basis of TRPM7 channelopathies and drug development. © 2023, The Author(s).},
	keywords = {MUTATION; INHIBITION; metabolism; ARTICLE; BINDING SITE; Cell Differentiation; Cell Differentiation; controlled study; Embryonic Development; Cryoelectron Microscopy; Protein Conformation; Protein Stability; PROTEIN FUNCTION; immune response; protein domain; molecular dynamics; protein structure; drug development; Structural stability; gain of function mutation; transient receptor potential channel M; transient receptor potential channel M7; TRPM Cation Channels; naltriben},
	year = {2023},
	eissn = {2041-1723}
}

@article{MTMT:34221622,
	title = {Cell death induction and protection by activation of ubiquitously expressed anion/cation channels. Part 3: the roles and properties of TRPM2 and TRPM7},
	url = {https://m2.mtmt.hu/api/publication/34221622},
	author = {Okada, Y. and Numata, T. and Sabirov, R.Z. and Kashio, M. and Merzlyak, P.G. and Sato-Numata, K.},
	doi = {10.3389/fcell.2023.1246955},
	journal-iso = {FRONT CELL DEV BIOL},
	journal = {FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY},
	volume = {11},
	unique-id = {34221622},
	issn = {2296-634X},
	abstract = {Cell volume regulation (CVR) is a prerequisite for animal cells to survive and fulfill their functions. CVR dysfunction is essentially involved in the induction of cell death. In fact, sustained normotonic cell swelling and shrinkage are associated with necrosis and apoptosis, and thus called the necrotic volume increase (NVI) and the apoptotic volume decrease (AVD), respectively. Since a number of ubiquitously expressed ion channels are involved in the CVR processes, these volume-regulatory ion channels are also implicated in the NVI and AVD events. In Part 1 and Part 2 of this series of review articles, we described the roles of swelling-activated anion channels called VSOR or VRAC and acid-activated anion channels called ASOR or PAC in CVR and cell death processes. Here, Part 3 focuses on therein roles of Ca2+-permeable non-selective TRPM2 and TRPM7 cation channels activated by stress. First, we summarize their phenotypic properties and molecular structure. Second, we describe their roles in CVR. Since cell death induction is tightly coupled to dysfunction of CVR, third, we focus on their participation in the induction of or protection against cell death under oxidative, acidotoxic, excitotoxic, and ischemic conditions. In this regard, we pay attention to the sensitivity of TRPM2 and TRPM7 to a variety of stress as well as to their capability to physicall and functionally interact with other volume-related channels and membrane enzymes. Also, we summarize a large number of reports hitherto published in which TRPM2 and TRPM7 channels are shown to be involved in cell death associated with a variety of diseases or disorders, in some cases as double-edged swords. Lastly, we attempt to describe how TRPM2 and TRPM7 are organized in the ionic mechanisms leading to cell death induction and protection. Copyright © 2023 Okada, Numata, Sabirov, Kashio, Merzlyak and Sato-Numata.},
	keywords = {APOPTOSIS; NECROSIS; Pyroptosis; TRPM2; TRPM7; cell volume regulation; oxidative cell death; acidotoxic cell death},
	year = {2023},
	eissn = {2296-634X}
}

@article{MTMT:34130650,
	title = {Regulation of ThermoTRP Channels by PIP2 and Cholesterol},
	url = {https://m2.mtmt.hu/api/publication/34130650},
	author = {Rosenbaum, T. and Morales-Lázaro, S.L.},
	doi = {10.1007/978-3-031-21547-6_9},
	journal-iso = {ADV EXP MED BIOL},
	journal = {ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY},
	volume = {1422},
	unique-id = {34130650},
	issn = {0065-2598},
	year = {2023},
	eissn = {2214-8019},
	pages = {245-277}
}

@article{MTMT:34064647,
	title = {Functional characterization of the transient receptor potential melastatin 2 (TRPM2) cation channel from Nematostella vectensis reconstituted into lipid bilayer},
	url = {https://m2.mtmt.hu/api/publication/34064647},
	author = {Szöllősi, András and Almássy, János},
	doi = {10.1038/s41598-023-38640-6},
	journal-iso = {SCI REP},
	journal = {SCIENTIFIC REPORTS},
	volume = {13},
	unique-id = {34064647},
	issn = {2045-2322},
	abstract = {Transient receptor potential melastatin 2 (TRPM2) cation channel activity is required for insulin secretion, immune cell activation and body heat control. Channel activation upon oxidative stress is involved in the pathology of stroke and neurodegenerative disorders. Cytosolic Ca 2+ , ADP-ribose (ADPR) and phosphatidylinositol-4,5-bisphosphate (PIP 2 ) are the obligate activators of the channel. Several TRPM2 cryo-EM structures have been resolved to date, yet functionality of the purified protein has not been tested. Here we reconstituted overexpressed and purified TRPM2 from Nematostella vectensis (nvTRPM2) into lipid bilayers and found that the protein is fully functional. Consistent with the observations in native membranes, nvTRPM2 in lipid bilayers is co-activated by cytosolic Ca 2+ and either ADPR or ADPR-2′-phosphate (ADPRP). The physiological metabolite ADPRP has a higher apparent affinity than ADPR. In lipid bilayers nvTRPM2 displays a large linear unitary conductance, its open probability (P o ) shows little voltage dependence and is stable over several minutes. P o is high without addition of exogenous PIP 2 , but is largely blunted by treatment with poly- l -Lysine, a polycation that masks PIP 2 headgroups. These results indicate that PIP 2 or some other activating phosphoinositol lipid co-purifies with nvTRPM2, suggesting a high PIP 2 binding affinity of nvTRPM2 under physiological conditions.},
	year = {2023},
	eissn = {2045-2322},
	orcid-numbers = {Szöllősi, András/0000-0002-5570-4609}
}

@article{MTMT:33848361,
	title = {Transient Receptor Potential (TRP) Channels in Pain, Neuropsychiatric Disorders, and Epilepsy},
	url = {https://m2.mtmt.hu/api/publication/33848361},
	author = {Yang, Felix and Sivils, Andy and Cegielski, Victoria and Singh, Som and Chu, Xiang-Ping},
	doi = {10.3390/ijms24054714},
	journal-iso = {INT J MOL SCI},
	journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
	volume = {24},
	unique-id = {33848361},
	issn = {1661-6596},
	abstract = {Pharmacomodulation of membrane channels is an essential topic in the study of physiological conditions and disease status. Transient receptor potential (TRP) channels are one such family of nonselective cation channels that have an important influence. In mammals, TRP channels consist of seven subfamilies with a total of twenty-eight members. Evidence shows that TRP channels mediate cation transduction in neuronal signaling, but the full implication and potential therapeutic applications of this are not entirely clear. In this review, we aim to highlight several TRP channels which have been shown to mediate pain sensation, neuropsychiatric disorders, and epilepsy. Recent findings suggest that TRPM (melastatin), TRPV (vanilloid), and TRPC (canonical) are of particular relevance to these phenomena. The research reviewed in this paper validates these TRP channels as potential targets of future clinical treatment and offers patients hope for more effective care.},
	keywords = {EPILEPSY; PAIN; DEPRESSION; Transient Receptor Potential Channels; seizure; BIPOLAR; TRP; TRPC; TRPV; TRPM},
	year = {2023},
	eissn = {1422-0067}
}

@article{MTMT:33655396,
	title = {The human ion channel TRPM2 modulates migration and invasion in neuroblastoma through regulation of integrin expression},
	url = {https://m2.mtmt.hu/api/publication/33655396},
	author = {Bao, L. and Festa, F. and Hirschler-Laszkiewicz, I. and Keefer, K. and Wang, H.-G. and Cheung, J.Y. and Miller, B.A.},
	doi = {10.1038/s41598-022-25138-w},
	journal-iso = {SCI REP},
	journal = {SCIENTIFIC REPORTS},
	volume = {12},
	unique-id = {33655396},
	issn = {2045-2322},
	abstract = {Transient receptor potential channel TRPM2 is highly expressed in many cancers and involved in regulation of key physiological processes including mitochondrial function, bioenergetics, and oxidative stress. In Stage 4 non-MYCN amplified neuroblastoma patients, high TRPM2 expression is associated with worse outcome. Here, neuroblastoma cells with high TRPM2 expression demonstrated increased migration and invasion capability. RNA sequencing, RT-qPCR, and Western blotting demonstrated that the mechanism involved significantly greater expression of integrins α1, αv, β1, and β5 in cells with high TRPM2 expression. Transcription factors HIF-1α, E2F1, and FOXM1, which bind promoter/enhancer regions of these integrins, were increased in cells with high TRPM2 expression. Subcellular fractionation confirmed high levels of α1, αv, and β1 membrane localization and co-immunoprecipitation confirmed the presence of α1β1, αvβ1, and αvβ5 complexes. Inhibitors of α1β1, αvβ1, and αvβ5 complexes significantly reduced migration and invasion in cells highly expressing TRPM2, confirming their functional role. Increased pAktSer473 and pERKThr202/Tyr204, which promote migration through mechanisms including integrin activation, were found in cells highly expressing TRPM2. TRPM2 promotes migration and invasion in neuroblastoma cells with high TRPM2 expression through modulation of integrins together with enhancing cell survival, negatively affecting patient outcome and providing rationale for TRPM2 inhibition in anti-neoplastic therapy. © 2022, The Author(s).},
	keywords = {Humans; INTEGRINS; GENETICS; human; Cell Survival; Cell Survival; NEUROBLASTOMA; NEUROBLASTOMA; integrin; Neoplasms, Second Primary; second cancer; Integrin alpha1; transient receptor potential channel M; TRPM Cation Channels; alpha1 integrin; TRPM2 protein, human},
	year = {2022},
	eissn = {2045-2322}
}

@article{MTMT:33262968,
	title = {Dual amplification strategy turns TRPM2 channels into supersensitive central heat detectors},
	url = {https://m2.mtmt.hu/api/publication/33262968},
	author = {Bartók, Ádám and Csanády, László},
	doi = {10.1073/pnas.2212378119},
	journal-iso = {P NATL ACAD SCI USA},
	journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
	volume = {119},
	unique-id = {33262968},
	issn = {0027-8424},
	abstract = {The Ca 2+ and ADP ribose (ADPR)-activated cation channel TRPM2 is the closest homolog of the cold sensor TRPM8 but serves as a deep-brain warmth sensor. To unravel the molecular mechanism of heat sensing by the TRPM2 protein, we study here temperature dependence of TRPM2 currents in cell-free membrane patches across ranges of agonist concentrations. We find that channel gating remains strictly agonist-dependent even at 40°C: heating alone or in combination with just Ca 2+ , just ADPR, Ca 2+ + cyclic ADPR, or H 2 O 2 pretreatment only marginally activates TRPM2. For fully liganded TRPM2, pore opening is intrinsically endothermic, due to ~10-fold larger activation enthalpy for opening (~200 kJ/mol) than for closure (~20 kJ/mol). However, the temperature threshold is too high (>40°C) for unliganded but too low (<15°C) for fully liganded channels. Thus, warmth sensitivity around 37°C is restricted to narrow ranges of agonist concentrations. For ADPR, that range matches, but for Ca 2+ , it exceeds bulk cytosolic values. The supraphysiological [Ca 2+ ] needed for TRPM2 warmth sensitivity is provided by Ca 2+ entering through the channel’s pore. That positive feedback provides further strong amplification to the TRPM2 temperature response (Q 10 ~ 1,000), enabling the TRPM2 protein to autonomously respond to tiny temperature fluctuations around 37°C. These functional data together with published structures suggest a molecular mechanism for opposite temperature dependences of two closely related channel proteins.},
	year = {2022},
	eissn = {1091-6490},
	orcid-numbers = {Bartók, Ádám/0000-0002-1232-5246; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:32657478,
	title = {Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels},
	url = {https://m2.mtmt.hu/api/publication/32657478},
	author = {Cheng, W.W.L. and Arcario, M.J. and Petroff, J.T. II},
	doi = {10.3389/fphys.2021.798102},
	journal-iso = {FRONT PHYSIOL},
	journal = {FRONTIERS IN PHYSIOLOGY},
	volume = {12},
	unique-id = {32657478},
	abstract = {Lipids modulate the function of many ion channels, possibly through direct lipid-protein interactions. The recent outpouring of ion channel structures by cryo-EM has revealed many lipid binding sites. Whether these sites mediate lipid modulation of ion channel function is not firmly established in most cases. However, it is intriguing that many of these lipid binding sites are also known sites for other allosteric modulators or drugs, supporting the notion that lipids act as endogenous allosteric modulators through these sites. Here, we review such lipid-drug binding sites, focusing on pentameric ligand-gated ion channels and transient receptor potential channels. Notable examples include sites for phospholipids and sterols that are shared by anesthetics and vanilloids. We discuss some implications of lipid binding at these sites including the possibility that lipids can alter drug potency or that understanding protein-lipid interactions can guide drug design. Structures are only the first step toward understanding the mechanism of lipid modulation at these sites. Looking forward, we identify knowledge gaps in the field and approaches to address them. These include defining the effects of lipids on channel function in reconstituted systems using asymmetric membranes and measuring lipid binding affinities at specific sites using native mass spectrometry, fluorescence binding assays, and computational approaches. Copyright © 2022 Cheng, Arcario and Petroff.},
	keywords = {transient receptor potential channel; molecular dynamics simulations; photoaffinity labeling; Allosteric modulation; cryo-EM; Native mass spectrometry; Pentameric ligand-gated ion channel; lipid binding sites},
	year = {2022},
	eissn = {1664-042X}
}

@article{MTMT:33408702,
	title = {Analysis of Gating Characteristics of TRPM8 Channel Based on Molecular Dynamics},
	url = {https://m2.mtmt.hu/api/publication/33408702},
	author = {Gao Zhiwei and Li Junwei and Shi Sai and Fu Qiang and Jia Junru and An Hailong},
	doi = {10.7503/cjcu20220080},
	journal-iso = {CHEM J CHINESE U},
	journal = {CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE},
	volume = {43},
	unique-id = {33408702},
	issn = {0251-0790},
	abstract = {Physiological functions of TRPM8 channel, such as temperature sensing, depend on normal gating. Due to the lack and insufficient number of existing crystal structures, the gating characteristics of TRPM8 channels need to be further explored. Therefore, 11 TRPM8 channels with different conformations were constructed, basing on the existing crystal structure and AlphaFold algorithm. It was found that there were two different architectural in the S6 transmembrane helical bundle crossing domain (gating) : loop state and helix state. At the loop state, multiple amino acids participated in the formation of pore regions that hinder ion permeability, while in the helical architecture. Only the key amino acid V956 played a gating role. Because the flexibility of the gated loop architecture was greater than that of the helical, and the number of key amino acids involved in gating was different. The secondary stricture prediction showed that the loop architecture could change to the helical. In this process, the flexible loop domain moved upward to the outside of the cell, and the gated amino acids twisted to the outside of the pore lining. At the same time, the interaction with the adjacent transmemhrane S5 helix was enhanced, and a rigid, stable and orderly helical architecture was formed. This promoted the coordination between the various domains of TRPM8 channel, enabled energy and information to be transmitted to the bundle crossing more efficiently, which was conducive to channel opening.},
	keywords = {Molecular Dynamics Simulation; Homology modeling; Gating mechanism; TRPM8 channel},
	year = {2022},
	eissn = {0251-0790}
}

@article{MTMT:32812324,
	title = {Structural mechanism of human TRPC3 and TRPC6 channel regulation by their intracellular calcium-binding sites},
	url = {https://m2.mtmt.hu/api/publication/32812324},
	author = {Guo, W. and Tang, Q. and Wei, M. and Kang, Y. and Wu, J.-X. and Chen, L.},
	doi = {10.1016/j.neuron.2021.12.023},
	journal-iso = {NEURON},
	journal = {NEURON},
	volume = {110},
	unique-id = {32812324},
	issn = {0896-6273},
	abstract = {TRPC3 and TRPC6 channels are calcium-permeable non-selective cation channels that are involved in many physiological processes. The gain-of-function (GOF) mutations of TRPC6 lead to familial focal segmental glomerulosclerosis (FSGS) in humans, but their pathogenic mechanism remains elusive. Here, we report the cryo-EM structures of human TRPC3 in both high-calcium and low-calcium conditions. Based on these structures and accompanying electrophysiological studies, we identified both inhibitory and activating calcium-binding sites in TRPC3 that couple intracellular calcium concentrations to the basal channel activity. These calcium sensors are also structurally and functionally conserved in TRPC6. We uncovered that the GOF mutations of TRPC6 activate the channel by allosterically abolishing the inhibitory effects of intracellular calcium. Furthermore, structures of human TRPC6 in complex with two chemically distinct inhibitors bound at different ligand-binding pockets reveal different conformations of the transmembrane domain, providing templates for further structure-based drug design targeting TRPC6-related diseases such as FSGS. © 2021 Elsevier Inc.},
	keywords = {Humans; metabolism; calcium; calcium; calcium; GENETICS; CALCIUM CHANNELS; BINDING SITES; BINDING SITE; human; pathology; calcium channel; transient receptor potential channel 6; focal glomerulosclerosis; Glomerulosclerosis, Focal Segmental; TRPC Cation Channels; transient receptor potential channel C; TRP channel; FSGS; TRPC channel; TRPC6; TRPC3; BTDM; SAR7334; TRPC6 protein, human; TRPC6 Cation Channel},
	year = {2022},
	eissn = {1097-4199},
	pages = {1023-1035.e5}
}

@article{MTMT:33289436,
	title = {Pathological Mechanisms Induced by TRPM2 Ion Channels Activation in Renal Ischemia-Reperfusion Injury},
	url = {https://m2.mtmt.hu/api/publication/33289436},
	author = {Khanahmad, H. and Mirbod, S.M. and karimi, F. and Kharazinejad, E. and Owjfard, M. and Najaflu, M. and Tavangar, M.},
	doi = {10.1007/s11033-022-07836-w},
	journal-iso = {MOL BIOL REP},
	journal = {MOLECULAR BIOLOGY REPORTS},
	volume = {49},
	unique-id = {33289436},
	issn = {0301-4851},
	abstract = {Renal ischemia-reperfusion (IR) injury triggers a cascade of signaling reactions involving an increase in Ca2 + charge and reactive oxygen species (ROS) levels resulting in necrosis, inflammation, apoptosis, and subsequently acute kidney injury (AKI). Transient receptor potential (TRP) channels include an essential class of Ca2+ permeable cation channels, which are segregated into six main channels: the canonical channel (TRPC), the vanilloid-related channel (TRPV), the melastatin-related channel (TRPM), the ankyrin-related channel (TRPA), the mucolipin-related channel (TRPML) and polycystin-related channel (TRPP) or polycystic kidney disease protein (PKD2). TRP channels are involved in adjusting vascular tone, vascular permeability, cell volume, proliferation, secretion, angiogenesis and apoptosis. TRPM channels include eight isoforms (TRPM1–TRPM8) and TRPM2 is the second member of this subfamily that has been expressed in various tissues and organs such as the brain, heart, kidney and lung. Renal TRPM2 channels have an important role in renal IR damage. So that TRPM2 deficient mice are resistant to renal IR injury. TRPM2 channels are triggered by several chemicals including hydrogen peroxide, Ca2+, and cyclic adenosine diphosphate (ADP) ribose (cADPR) that are generated during AKI caused by IR injury, as well as being implicated in cell death caused by oxidative stress, inflammation, and apoptosis. © 2022, The Author(s), under exclusive licence to Springer Nature B.V.},
	keywords = {Animals; Inflammation; Inflammation; APOPTOSIS; metabolism; calcium; calcium; MICE; GENETICS; KIDNEY; KIDNEY; REPERFUSION INJURY; REPERFUSION INJURY; MOUSE; signal transduction; review; animal; clinical feature; nonhuman; Transient Receptor Potential Channels; transient receptor potential channel; protein expression; ischemia-reperfusion; complex formation; acute kidney failure; acute kidney injury; acute kidney injury; TRP; transient receptor potential channel M; transient receptor potential channel M2; TRPM Cation Channels; TRPM2; renal ischemia reperfusion injury; Oxidative stress; Oxidative stress; TRPM2 protein, mouse; Oxidative stress, and inflammation},
	year = {2022},
	eissn = {1573-4978},
	pages = {11071-11079}
}

@article{MTMT:33289437,
	title = {The identification of the key residues E829 and R845 involved in transient receptor potential melastatin 2 channel gating},
	url = {https://m2.mtmt.hu/api/publication/33289437},
	author = {Luo, Y. and Chen, S. and Wu, F. and Jiang, C. and Fang, M.},
	doi = {10.3389/fnagi.2022.1033434},
	journal-iso = {FRONT AGING NEUROSCI},
	journal = {FRONTIERS IN AGING NEUROSCIENCE},
	volume = {14},
	unique-id = {33289437},
	issn = {1663-4365},
	abstract = {Transient receptor potential melastatin 2 (TRPM2), a non-selective cation channel, is involved in many physiological and pathological processes, including temperature sensing, synaptic plasticity regulation, and neurodegenerative diseases. However, the gating mechanism of TRPM2 channel is complex, which hinders its functional research. With the discovery of the Ca2+ binding site in the S2–S3 domain of TRPM2 channel, more and more attention has been drawn to the role of the transmembrane segments in channel gating. In this study, we focused on the D820-F867 segment around the S2 domain, and identified the key residues on it. Functional assays of the deletion mutants displayed that the deletions of D820-W835 and L836-P851 destroyed channel function totally, indicating the importance of these two segments. Sequence alignments on them found three polar and charged residues with high conservation (D820, E829, and R845). D820A, E829A, and R845A which removed the charge and the side chain of the residues were tested by 500 μM adenosine diphosphate-ribose (ADPR) or 50 mM Ca2+. E829A and R845A affected the characteristic of channel currents, while D820A behaved similarly to WT, indicating the participations of E829 and R845 in channel gating. The charge reversing mutants, E829K and R845D were then constructed and the electrophysiological tests showed that E829A and E829K made the channel lose function. Interestingly, R845A and R845D exhibited an inactivation process when using 500 μM ADPR, but activated normally by 50 mM Ca2+. Our data suggested that the negative charge at E829 took a vital part in channel activation, and R845 increased the stability of the Ca2+ combination in S2-S3 domain, thus guaranteeing the opening of TRPM2 channel. In summary, our identification of the key residues E829 and R845 in the transmembrane segments of TRPM2. By exploring the gating process of TRPM2 channel, our work helps us better understand the mechanism of TRPM2 as a potential biomarker in neurodegenerative diseases, and provides a new approach for the prediction, diagnosis, and prognosis of neurodegenerative diseases. Copyright © 2022 Luo, Chen, Wu, Jiang and Fang.},
	keywords = {INACTIVATION; ACTIVATION; LYSINE; ARTICLE; BINDING SITE; PREDICTION; human; Electrophysiology; Prognosis; arginine; controlled study; LEUCINE; Sequence Alignment; Calcium ion; biological marker; glutamic acid; embryo; human cell; unclassified drug; tryptophan; PROLINE; protein domain; ALANINE; aspartic acid; degenerative disease; loss of function mutation; calcium binding; adenosine diphosphate ribose; channel gating; Gating mechanism; key residues; Transmembrane segments; transient receptor potential channel M; TRPM2; Transient receptor potential melastatin 2},
	year = {2022},
	eissn = {1663-4365}
}

@article{MTMT:32729897,
	title = {The Role of Lipids in CRAC Channel Function},
	url = {https://m2.mtmt.hu/api/publication/32729897},
	author = {Maltan, L. and Andova, A.-M. and Derler, I.},
	doi = {10.3390/biom12030352},
	journal-iso = {BIOMOLECULES},
	journal = {BIOMOLECULES},
	volume = {12},
	unique-id = {32729897},
	issn = {2218-273X},
	abstract = {The composition and dynamics of the lipid membrane define the physical properties of the bilayer and consequently affect the function of the incorporated membrane transporters, which also applies for the prominent Ca2+ release-activated Ca2+ ion channel (CRAC). This channel is activated by receptor-induced Ca2+ store depletion of the endoplasmic reticulum (ER) and consists of two transmembrane proteins, STIM1 and Orai1. STIM1 is anchored in the ER membrane and senses changes in the ER luminal Ca2+ concentration. Orai1 is the Ca2+-selective, pore-forming CRAC channel component located in the plasma membrane (PM). Ca2+ store-depletion of the ER triggers activation of STIM1 proteins, which subsequently leads to a conformational change and oligomerization of STIM1 and its coupling to as well as activation of Orai1 channels at the ER-PM contact sites. Although STIM1 and Orai1 are sufficient for CRAC channel activation, their efficient activation and deactivation is fine-tuned by a variety of lipids and lipid-and/or ER-PM junctiondependent accessory proteins. The underlying mechanisms for lipid-mediated CRAC channel modulation as well as the still open questions, are presented in this review. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.},
	keywords = {LIPIDS; STIM1; ER-PM junctions; Protein-lipid interactions; Orai1; CRAC channel; Modulatory proteins},
	year = {2022},
	eissn = {2218-273X}
}

@article{MTMT:32657479,
	title = {It takes two to Tango: Two gates orchestrate the opening of human TRPM2},
	url = {https://m2.mtmt.hu/api/publication/32657479},
	author = {Rish, A.D. and Shen, Z. and Fu, T.-M.},
	doi = {10.1016/j.ceca.2021.102523},
	journal-iso = {CELL CALCIUM},
	journal = {CELL CALCIUM},
	volume = {101},
	unique-id = {32657479},
	issn = {0143-4160},
	abstract = {TRPM2 is a calcium permeable non-selective cation channel involved in many important physiological processes and has divergent gating mechanisms across species. Structural studies have revealed that TRPM2 is gated by adenosine 5′-diphosphoribose that binds to the cytosolic domains of TRPM2 and calcium ions that are coordinated by residues in the transmembrane domain. However, the selectivity filter of human TRPM2 remains elusive due to the poor resolution in this region. In a recent manuscript published in Cell Reports, Yu et al. present unexpected dual roles of the selectivity filter in human TRPM2 by determining a high-resolution structure of human TRPM2 in lipid nanodiscs. This study provides unprecedented insights into the gating mechanism of human TRPM2. © 2021 Elsevier Ltd},
	keywords = {Humans; metabolism; calcium; calcium; human; protein domain; Ion Channel Gating; adenosine diphosphate ribose; adenosine diphosphate ribose; channel gating; Protein Domains; transient receptor potential channel M; TRPM Cation Channels; TRPM2 protein, human},
	year = {2022},
	eissn = {1532-1991}
}

@article{MTMT:32812322,
	title = {Structural mechanism of TRPM7 channel regulation by intracellular magnesium},
	url = {https://m2.mtmt.hu/api/publication/32812322},
	author = {Schmidt, E. and Narangoda, C. and Nörenberg, W. and Egawa, M. and Rössig, A. and Leonhardt, M. and Schaefer, M. and Zierler, S. and Kurnikova, M.G. and Gudermann, T. and Chubanov, V.},
	doi = {10.1007/s00018-022-04192-7},
	journal-iso = {CELL MOL LIFE SCI},
	journal = {CELLULAR AND MOLECULAR LIFE SCIENCES},
	volume = {79},
	unique-id = {32812322},
	issn = {1420-682X},
	abstract = {Zn2+, Mg2+ and Ca2+ are essential divalent cations implicated in many metabolic processes and signalling pathways. An emerging new paradigm is that the organismal balance of these cations predominantly depends on a common gatekeeper, the channel-kinase TRPM7. Despite extensive electrophysiological studies and recent cryo-EM analysis, an open question is how the channel activity of TRPM7 is activated. Here, we performed site-directed mutagenesis of mouse TRPM7 in conjunction with patch-clamp assessment of whole-cell and single-channel activity and molecular dynamics (MD) simulations to show that the side chains of conserved N1097 form an inter-subunit Mg2+ regulatory site located in the lower channel gate of TRPM7. Our results suggest that intracellular Mg2+ binds to this site and stabilizes the TRPM7 channel in the closed state, whereas the removal of Mg2+ favours the opening of TRPM7. Hence, our study identifies the structural underpinnings through which the TRPM7 channel is controlled by cytosolic Mg2+, representing a new structure–function relationship not yet explored among TRPM channels. © 2022, The Author(s).},
	keywords = {MAGNESIUM; ATP; molecular dynamics simulations; TRP CHANNELS; PIP2; TRPM7},
	year = {2022},
	eissn = {1420-9071}
}

@article{MTMT:32793001,
	title = {On the Connections between TRPM Channels and SOCE},
	url = {https://m2.mtmt.hu/api/publication/32793001},
	author = {Sousza, Bomfim G.H. and Niemeyer, B.A. and Lacruz, R.S. and Lis, A.},
	doi = {10.3390/cells11071190},
	journal-iso = {CELLS-BASEL},
	journal = {CELLS},
	volume = {11},
	unique-id = {32793001},
	abstract = {Plasma membrane protein channels provide a passageway for ions to access the intracellular milieu. Rapid entry of calcium ions into cells is controlled mostly by ion channels, while Ca2+-ATPases and Ca2+ exchangers ensure that cytosolic Ca2+ levels ([Ca2+ ]cyt) are maintained at low (~100 nM) concentrations. Some channels, such as the Ca2+-release-activated Ca2+ (CRAC) channels and voltagedependent Ca2+ channels (CACNAs), are highly Ca2+-selective, while others, including the Transient Receptor Potential Melastatin (TRPM) family, have broader selectivity and are mostly permeable to monovalent and divalent cations. Activation of CRAC channels involves the coupling between ORAI1-3 channels with the endoplasmic reticulum (ER) located Ca2+ store sensor, Stromal Interaction Molecules 1-2 (STIM1/2), a pathway also termed store-operated Ca2+ entry (SOCE). The TRPM family is formed by 8 members (TRPM1-8) permeable to Mg2+, Ca2+, Zn2+ and Na+ cations, and is activated by multiple stimuli. Recent studies indicated that SOCE and TRPM structure-function are interlinked in some instances, although the molecular details of this interaction are only emerging. Here we review the role of TRPM and SOCE in Ca2+ handling and highlight the available evidence for this interaction. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.},
	keywords = {PHOSPHORYLATION; calcium; calcium; CALCIUM CHANNELS; Neuropathic pain; review; human; Electrophysiology; neutrophil; endoplasmic reticulum; Calcium ion; protein phosphorylation; action potential; Transient Receptor Potential Channels; transient receptor potential channel; Adenosine Triphosphate; Circular Dichroism; cyclic GMP; structure activity relation; calcium channel; Calcium Signaling; calcium transport; G protein coupled receptor; calcium homeostasis; protein kinase C alpha; Ca2+ signaling; channel gating; myosin heavy chain; Smad2 protein; transient receptor potential channel M4; transient receptor potential channel M8; stromal interaction molecule 1; calcium release activated calcium channel 1; transient receptor potential channel M3; AMPK signaling; calcium release activated calcium channel; ORAI1 Protein; lipocortin 1; clusterin; store operated calcium entry; transient receptor potential channel M; transient receptor potential channel M1; transient receptor potential channel M6; transient receptor potential channel M7; SOCE; TRPM Cation Channels; stromal interaction molecule 2; TRPM channels; transient receptor potential channel M5; Orai channels; Calcium Release Activated Calcium Channels},
	year = {2022},
	eissn = {2073-4409}
}

@article{MTMT:33305830,
	title = {Ligand-Binding Sites in Vanilloid-Subtype TRP Channels},
	url = {https://m2.mtmt.hu/api/publication/33305830},
	author = {Yelshanskaya, Maria V. and Sobolevsky, Alexander I.},
	doi = {10.3389/fphar.2022.900623},
	journal-iso = {FRONT PHARMACOL},
	journal = {FRONTIERS IN PHARMACOLOGY},
	volume = {13},
	unique-id = {33305830},
	abstract = {Vanilloid-subfamily TRP channels TRPV1-6 play important roles in various physiological processes and are implicated in numerous human diseases. Advances in structural biology, particularly the "resolution revolution" in cryo-EM, have led to breakthroughs in molecular characterization of TRPV channels. Structures with continuously improving resolution uncover atomic details of TRPV channel interactions with small molecules and protein-binding partners. Here, we provide a classification of structurally characterized binding sites in TRPV channels and discuss the progress that has been made by structural biology combined with mutagenesis, functional recordings, and molecular dynamics simulations toward understanding of the molecular mechanisms of ligand action. Given the similarity in structural architecture of TRP channels, 16 unique sites identified in TRPV channels may be shared between TRP channel subfamilies, although the chemical identity of a particular ligand will likely depend on the local amino-acid composition. The characterized binding sites and molecular mechanisms of ligand action create a diversity of druggable targets to aid in the design of new molecules for tuning TRP channel function in disease conditions.},
	keywords = {ANTAGONIST; INHIBITOR; LIGAND; AGONIST; X-RAY CRYSTALLOGRAPHY; TRP CHANNELS; cryo-EM; blocker},
	year = {2022},
	eissn = {1663-9812}
}

@article{MTMT:32657389,
	title = {A Systemic Review of the Integral Role of TRPM2 in Ischemic Stroke: From Upstream Risk Factors to Ultimate Neuronal Death},
	url = {https://m2.mtmt.hu/api/publication/32657389},
	author = {Zong, P. and Lin, Q. and Feng, J. and Yue, L.},
	doi = {10.3390/cells11030491},
	journal-iso = {CELLS-BASEL},
	journal = {CELLS},
	volume = {11},
	unique-id = {32657389},
	abstract = {Ischemic stroke causes a heavy health burden worldwide, with over 10 million new cases every year. Despite the high prevalence and mortality rate of ischemic stroke, the underlying molecular mechanisms for the common etiological factors of ischemic stroke and ischemic stroke itself remain unclear, which results in insufficient preventive strategies and ineffective treatments for this devastating disease. In this review, we demonstrate that transient receptor potential cation channel, subfamily M, member 2 (TRPM2), a non-selective ion channel activated by oxidative stress, is actively involved in all the important steps in the etiology and pathology of ischemic stroke. TRPM2 could be a promising target in screening more effective prophylactic strategies and therapeutic medications for ischemic stroke. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.},
	keywords = {Inflammation; PREVALENCE; ISCHEMIA; CYTOKINE PRODUCTION; CYTOTOXICITY; review; human; diabetes mellitus; Cell Survival; MACROPHAGE; risk factor; HYPERTENSION; cell infiltration; brain ischemia; cognition; Insulin Resistance; drug delivery system; endothelial dysfunction; Tumor Necrosis Factor; cerebrovascular disease; immune response; reactive oxygen metabolite; ischemic stroke; ischemic stroke; systematic review; microglia; endothelium cell; interleukin 1beta; cognitive defect; blood brain barrier; Calcium Signaling; atherosclerotic plaque; brain development; ASTROCYTE; blood clot lysis; common carotid artery; Ca2+ signaling; cell invasion; Middle cerebral artery occlusion; Atrial Fibrillation; macrophage migration; mortality rate; transient receptor potential channel M2; TRPM2; Oxidative stress; Oxidative stress},
	year = {2022},
	eissn = {2073-4409}
}

@article{MTMT:32915252,
	title = {Functional coupling of TRPM2 and extrasynaptic NMDARs exacerbates excitotoxicity in ischemic brain injury},
	url = {https://m2.mtmt.hu/api/publication/32915252},
	author = {Zong, P. and Feng, J. and Yue, Z. and Li, Y. and Wu, G. and Sun, B. and He, Y. and Miller, B. and Yu, A.S. and Su, Z. and Xie, J. and Mori, Y. and Hao, B. and Yue, L.},
	doi = {10.1016/j.neuron.2022.03.021},
	journal-iso = {NEURON},
	journal = {NEURON},
	volume = {110},
	unique-id = {32915252},
	issn = {0896-6273},
	abstract = {Excitotoxicity induced by NMDA receptor (NMDAR) activation is a major cause of neuronal death in ischemic stroke. However, past efforts of directly targeting NMDARs have unfortunately failed in clinical trials. Here, we reveal an unexpected mechanism underlying NMDAR-mediated neurotoxicity, which leads to the identification of a novel target and development of an effective therapeutic peptide for ischemic stroke. We show that NMDAR-induced excitotoxicity is enhanced by physical and functional coupling of NMDAR to an ion channel TRPM2 upon ischemic insults. TRPM2-NMDAR association promotes the surface expression of extrasynaptic NMDARs, leading to enhanced NMDAR activity and increased neuronal death. We identified a specific NMDAR-interacting motif on TRPM2 and designed a membrane-permeable peptide to uncouple the TRPM2-NMDAR interaction. This disrupting peptide protects neurons against ischemic injury in vitro and protects mice against ischemic stroke in vivo. These findings provide an unconventional strategy to mitigate excitotoxic neuronal death without directly targeting NMDARs. © 2022 Elsevier Inc.},
	keywords = {Animals; PEPTIDES; metabolism; PEPTIDE; MICE; GENETICS; NMDA RECEPTORS; MOUSE; animal; brain ischemia; n methyl dextro aspartic acid receptor; Brain Injuries; excitotoxicity; ischemic stroke; ischemic stroke; Receptors, N-Methyl-D-Aspartate; NEURONAL DEATH; brain injury; Ca2+ signaling; N-Methylaspartate; n methylaspartic acid; transient receptor potential channel M; TRPM Cation Channels; TRPM2; NMDARs; therapeutic peptide; TRPM2 protein, mouse},
	year = {2022},
	eissn = {1097-4199},
	pages = {1944-1958.e8}
}

@article{MTMT:31739238,
	title = {Temperature-sensitive transient receptor potential vanilloid channels: structural insights into ligand-dependent activation},
	url = {https://m2.mtmt.hu/api/publication/31739238},
	author = {Zubcevic, Lejla},
	doi = {10.1111/bph.15310},
	journal-iso = {BR J PHARMACOL},
	journal = {BRITISH JOURNAL OF PHARMACOLOGY},
	volume = {179},
	unique-id = {31739238},
	issn = {0007-1188},
	abstract = {Temperature-sensitive transient receptor potential vanilloid ion channel subtypes 1-4 (thermoTRPV1-thermoTRPV4) play important roles in a wide range of physiological processes, including temperature sensing and body temperature regulation, inflammation, pain, itch, maintenance of skin, bone and hair, along with osmotic regulation. ThermoTRPV function is modulated by numerous natural product compounds, such as capsaicin, camphor and cannabinoids. Because of their physiological importance and their druggability, these channels have made attractive potential targets for drug development. Since the beginning of the cryo-electron miscroscopy (cryo-EM) "resolution revolution," a lot of progress has been made towards dissecting the activation mechanisms of thermoTRPVs and mapping the binding sites for modulatory compounds. Here, we review the thermoTRPV physiology and pharmacology and summarize the current knowledge of their mechanisms of gating and ligand binding sites.},
	keywords = {BINDING SITE; ion channel; Drug target; natural product; Membrane transport; EM; TRPV CHANNEL; cryo‐},
	year = {2022},
	eissn = {1476-5381},
	pages = {3542-3559}
}

@article{MTMT:32199335,
	title = {Trpm2 non-selective cation channels in liver injury mediated by reactive oxygen species},
	url = {https://m2.mtmt.hu/api/publication/32199335},
	author = {Ali, E.S. and Rychkov, G.Y. and Barritt, G.J.},
	doi = {10.3390/antiox10081243},
	journal-iso = {ANTIOXIDANTS-BASEL},
	journal = {ANTIOXIDANTS},
	volume = {10},
	unique-id = {32199335},
	abstract = {TRPM2 channels admit Ca2+ and Na+ across the plasma membrane and release Ca2+ and Zn2+ from lysosomes. Channel activation is initiated by reactive oxygen species (ROS), leading to a subsequent increase in ADP-ribose and the binding of ADP-ribose to an allosteric site in the cytosolic NUDT9 homology domain. In many animal cell types, Ca2+ entry via TRPM2 channels mediates ROS-initiated cell injury and death. The aim of this review is to summarise the current knowledge of the roles of TRPM2 and Ca2+ in the initiation and progression of chronic liver diseases and acute liver injury. Studies to date provide evidence that TRPM2-mediated Ca2+ entry contributes to drug-induced liver toxicity, ischemia–reperfusion injury, and the progression of non-alcoholic fatty liver disease to cirrhosis, fibrosis, and hepatocellular carcinoma. Of particular current interest are the steps involved in the activation of TRPM2 in hepatocytes following an increase in ROS, the downstream pathways activated by the resultant increase in intracellular Ca2+, and the chronology of these events. An apparent contradiction exists between these roles of TRPM2 and the role identified for ROS-activated TRPM2 in heart muscle and in some other cell types in promoting Ca2+-activated mitochondrial ATP synthesis and cell survival. Inhibition of TRPM2 by curcumin and other “natural” compounds offers an attractive strategy for inhibiting ROS-induced liver cell injury. In conclusion, while it has been established that ROS-initiated activation of TRPM2 contributes to both acute and chronic liver injury, considerable further research is needed to elucidate the mechanisms involved, and the conditions under which pharmacological inhibition of TRPM2 can be an effective clinical strategy to reduce ROS-initiated liver injury. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.},
	keywords = {LIVER; CA2+; Reactive oxygen species; ACETAMINOPHEN; ischemia-reperfusion; CURCUMIN; Non-Alcoholic Fatty Liver Disease; TRPM2 CHANNELS},
	year = {2021},
	eissn = {2076-3921}
}

@article{MTMT:32008293,
	title = {Species-specific regulation of trpm2 by pi(4,5)p2 via the membrane interfacial cavity},
	url = {https://m2.mtmt.hu/api/publication/32008293},
	author = {Barth, D. and Lückhoff, A. and Kühn, F.J.P.},
	doi = {10.3390/ijms22094637},
	journal-iso = {INT J MOL SCI},
	journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
	volume = {22},
	unique-id = {32008293},
	issn = {1661-6596},
	abstract = {The human apoptosis channel TRPM2 is stimulated by intracellular ADR-ribose and cal-cium. Recent studies show pronounced species-specific activation mechanisms. Our aim was to an-alyse the functional effect of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), commonly referred to as PIP2, on different TRPM2 orthologues. Moreover, we wished to identify the interaction site between TRPM2 and PIP2. We demonstrate a crucial role of PIP2, in the activation of TRPM2 orthologues of man, zebrafish, and sea anemone. Utilizing inside-out patch clamp recordings of HEK-293 cells transfected with TRPM2, differential effects of PIP2 that were dependent on the species variant became apparent. While depletion of PIP2 via polylysine uniformly caused complete inactivation of TRPM2, restoration of channel activity by artificial PIP2 differed widely. Human TRPM2 was the least sensitive species variant, making it the most susceptible one for regulation by changes in intramembranous PIP2 content. Furthermore, mutations of highly conserved positively charged amino acid residues in the membrane interfacial cavity reduced the PIP2 sensitivity in all three TRPM2 orthologues to varying degrees. We conclude that the membrane interfacial cavity acts as a uniform PIP2 binding site of TRPM2, facilitating channel activation in the presence of ADPR and Ca2+ in a species-specific manner. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.},
	keywords = {phospholipid; patch clamp; Phosphoinositides; PIP2; TRPM2},
	year = {2021},
	eissn = {1422-0067}
}

@article{MTMT:32593218,
	title = {TRPA1: Pharmacology, natural activators and role in obesity prevention},
	url = {https://m2.mtmt.hu/api/publication/32593218},
	author = {Mahajan, Neha and Khare, Pragyanshu and Kondepudi, Kanthi Kiran and Bishnoi, Mahendra},
	doi = {10.1016/j.ejphar.2021.174553},
	journal-iso = {EUR J PHARMACOL},
	journal = {EUROPEAN JOURNAL OF PHARMACOLOGY},
	volume = {912},
	unique-id = {32593218},
	issn = {0014-2999},
	abstract = {Transient receptor potential ankyrin 1 (TRPA1) channel is a calcium permeable, non-selective cation channel, expressed in the sensory neurons and non-neuronal cells of different tissues. Initially studied for its role in pain and inflammation, TRPA1 has now functionally involved in multiple other physiological functions. TRPA1 channel has been extensively studied for modulation by pungent compounds present in the spices and herbs. In the last decade, the role of TRPA1 agonism in body weight reduction, secretion of hunger and satiety hormones, insulin secretion and thermogenesis, has unveiled the potential of the TRPA1 channel to be used as a preventive target to tackle obesity and associated comorbidities including insulin resistance in type 2 diabetes. In this review, we summarized the recent findings of TRPA1 based dietary/non-dietary modulation for its role in obesity prevention and therapeutics.},
	keywords = {BROWN ADIPOSE-TISSUE; ION-CHANNEL; INSULIN-RESISTANCE; INSULIN; allyl isothiocyanate; Diet-induced obesity; gut hormones; HIGH-FAT; Calcium-sensing receptor; transient receptor potential; RECEPTOR POTENTIAL CHANNELS; Dietary modulators; CAUSES PAIN SENSATION},
	year = {2021},
	eissn = {1879-0712}
}

@article{MTMT:32657480,
	title = {Mechanism of praziquantel action at a parasitic flatworm ion channel},
	url = {https://m2.mtmt.hu/api/publication/32657480},
	author = {Park, S.-K. and Friedrich, L. and Yahya, N.A. and Rohr, C.M. and Chulkov, E.G. and Maillard, D. and Rippmann, F. and Spangenberg, T. and Marchant, J.S.},
	doi = {10.1126/scitranslmed.abj5832},
	journal-iso = {SCI TRANSL MED},
	journal = {SCIENCE TRANSLATIONAL MEDICINE},
	volume = {13},
	unique-id = {32657480},
	issn = {1946-6234},
	abstract = {Praziquantel (PZQ) is an essential medicine for treating parasitic flatworm infections such as schistosomiasis, which afflicts over 250 million people. However, PZQ is not universally effective, lacking activity against liver flukes of the Fasciola genus. The reason for this insensitivity is unclear, as the mechanism of PZQ action is unknown. Here, we use ligand- and target-based methods to demonstrate that PZQ activates a transient receptor potential melastatin ion channel (TRPMPZQ) in schistosomes by engaging a hydrophobic ligand binding pocket within the voltage sensor-like domain of the channel to cause calcium entry and worm paralysis. PZQ activates TRPMPZQ homologs in other PZQ-sensitive flukes, but not Fasciola hepatica. However, a single amino acid change in the F. hepatica TRPMPZQ binding pocket, to mimic schistosome TRPMPZQ, confers PZQ sensitivity. After decades of clinical use, the molecular basis of PZQ action at a druggable TRP channel is resolved. © 2021 The Authors.},
	year = {2021},
	eissn = {1946-6242}
}

@article{MTMT:32199337,
	title = {Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition},
	url = {https://m2.mtmt.hu/api/publication/32199337},
	author = {Ruan, Z. and Haley, E. and Orozco, I.J. and Sabat, M. and Myers, R. and Roth, R. and Du, J. and Lü, W.},
	doi = {10.1038/s41594-021-00607-4},
	journal-iso = {NAT STRUCT MOL BIOL},
	journal = {NATURE STRUCTURAL & MOLECULAR BIOLOGY},
	volume = {28},
	unique-id = {32199337},
	issn = {1545-9993},
	abstract = {The Ca2+-activated TRPM5 channel plays essential roles in taste perception and insulin secretion. However, the mechanism by which Ca2+ regulates TRPM5 activity remains elusive. We report cryo-EM structures of the zebrafish TRPM5 in an apo closed state, a Ca2+-bound open state, and an antagonist-bound inhibited state. We define two novel ligand binding sites: a Ca2+ site (CaICD) in the intracellular domain and an antagonist site in the transmembrane domain (TMD). The CaICD site is unique to TRPM5 and has two roles: modulating the voltage dependence and promoting Ca2+ binding to the CaTMD site, which is conserved throughout TRPM channels. Conformational changes initialized from both Ca2+ sites cooperatively open the ion-conducting pore. The antagonist NDNA wedges into the space between the S1–S4 domain and pore domain, stabilizing the transmembrane domain in an apo-like closed state. Our results lay the foundation for understanding the voltage-dependent TRPM channels and developing new therapeutic agents. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.},
	keywords = {ARTICLE; signal transduction; BINDING SITE; human; Electrophysiology; controlled study; nonhuman; Calcium ion; Cryoelectron Microscopy; Conserved Sequence; Protein Conformation; human cell; amino terminal sequence; ligand binding; protein structure; hydrogen bond; alpha helix; conformational transition; calcium binding; channel gating; zebra fish; orthology; tetramerization; inside out patch clamp; transient receptor potential channel M5},
	year = {2021},
	eissn = {1545-9985},
	pages = {604-613}
}

@article{MTMT:32199343,
	title = {Transient Receptor Potential Ankyrin 1 Channel: An Evolutionarily Tuned Thermosensor},
	url = {https://m2.mtmt.hu/api/publication/32199343},
	author = {Sinica, V. and Vlachová, V.},
	doi = {10.33549/physiolres.934697},
	journal-iso = {PHYSIOL RES},
	journal = {PHYSIOLOGICAL RESEARCH},
	volume = {70},
	unique-id = {32199343},
	issn = {0862-8408},
	abstract = {The discovery of the role of the transient receptor potential ankyrin 1 (TRPA1) channel as a polymodal detector of cold and pain-producing stimuli almost two decades ago catalyzed the consequent identification of various vertebrate and invertebrate orthologues. In different species, the role of TRPA1 has been implicated in numerous physiological functions, indicating that the molecular structure of the channel exhibits evolutionary flexibility. Until very recently, information about the critical elements of the temperature-sensing molecular machinery of thermosensitive ion channels such as TRPA1 had lagged far behind information obtained from mutational and functional analysis. Current developments in single-particle cryo-electron microscopy are revealing precisely how the thermosensitive channels operate, how they might be targeted with drugs, and at which sites they can be critically regulated by membrane lipids. This means that it is now possible to resolve a huge number of very important pharmacological, biophysical and physiological questions in a way we have never had before. In this review, we aim at providing some of the recent knowledge on the molecular mechanisms underlying the temperature sensitivity of TRPA1. We also demonstrate how the search for differences in temperature and chemical sensitivity between human and mouse TRPA1 orthologues can be a useful approach to identifying important domains with a key role in channel activation. © 2021 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic},
	keywords = {noxious heat; structure-function; Functional diversity; Transient receptor potential ankyrin 1; Gating models; Noxious cold},
	year = {2021},
	eissn = {1802-9973},
	pages = {363-381}
}

@article{MTMT:32040119,
	title = {Two decades of evolution of our understanding of the transient receptor potential melastatin 2 (Trpm2) cation channel},
	url = {https://m2.mtmt.hu/api/publication/32040119},
	author = {Szöllősi, András},
	doi = {10.3390/life11050397},
	journal-iso = {LIFE-BASEL},
	journal = {LIFE-BASEL},
	volume = {11},
	unique-id = {32040119},
	abstract = {The transient receptor potential melastatin (TRPM) family belongs to the superfamily of TRP ion channels. It consists of eight family members that are involved in a plethora of cellular functions. TRPM2 is a homotetrameric Ca2+-permeable cation channel activated upon oxidative stress and is important, among others, for body heat control, immune cell activation and insulin secretion. Invertebrate TRPM2 proteins are channel enzymes; they hydrolyze the activating ligand, ADP-ribose, which is likely important for functional regulation. Since its cloning in 1998, the understanding of the biophysical properties of the channel has greatly advanced due to a vast number of structure– function studies. The physiological regulators of the channel have been identified and characterized in cell-free systems. In the wake of the recent structural biochemistry revolution, several TRPM2 cryo-EM structures have been published. These structures have helped to understand the general features of the channel, but at the same time have revealed unexplained mechanistic differences among channel orthologues. The present review aims at depicting the major research lines in TRPM2 structure-function. It discusses biophysical properties of the pore and the mode of action of direct channel effectors, and interprets these functional properties on the basis of recent three-dimensional structural models. © 2021 by the author. Licensee MDPI, Basel, Switzerland.},
	keywords = {ION CHANNELS; ADP-ribose; Single particle cryo-EM; TRPM2; Nudix hydrolase},
	year = {2021},
	eissn = {2075-1729},
	orcid-numbers = {Szöllősi, András/0000-0002-5570-4609}
}

@article{MTMT:32657481,
	title = {Structural and functional basis of the selectivity filter as a gate in human TRPM2 channel},
	url = {https://m2.mtmt.hu/api/publication/32657481},
	author = {Yu, X. and Xie, Y. and Zhang, X. and Ma, C. and Liu, L. and Zhen, W. and Xu, L. and Zhang, J. and Liang, Y. and Zhao, L. and Gao, X. and Yu, P. and Luo, J. and Jiang, L.-H. and Nie, Y. and Yang, F. and Guo, J. and Yang, W.},
	doi = {10.1016/j.celrep.2021.110025},
	journal-iso = {CELL REP},
	journal = {CELL REPORTS},
	volume = {37},
	unique-id = {32657481},
	issn = {2211-1247},
	abstract = {Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable cation channel, is gated by intracellular adenosine diphosphate ribose (ADPR), Ca2+, warm temperature, and oxidative stress. It is critically involved in physiological and pathological processes ranging from inflammation to stroke to neurodegeneration. At present, the channel's gating and ion permeation mechanisms, such as the location and identity of the selectivity filter, remain ambiguous. Here, we report the cryo-electron microscopy (cryo-EM) structure of human TRPM2 in nanodisc in the ligand-free state. Cryo-EM map-guided computational modeling and patch-clamp recording further identify a quadruple-residue motif as the ion selectivity filter, which adopts a restrictive conformation in the closed state and acts as a gate, profoundly contrasting with its widely open conformation in the Nematostella vectensis TRPM2. Our study reveals the gating of human TRPM2 by the filter and demonstrates the feasibility of using cryo-EM in conjunction with computational modeling and functional studies to garner structural information for intrinsically dynamic but functionally important domains. © 2021 The Authors},
	keywords = {calcium; ARTICLE; human; controlled study; nonhuman; species difference; Cryoelectron Microscopy; human cell; ion transport; protein structure; conformational transition; computer model; adenosine diphosphate; protein motif; channel gating; Computational modeling; HEK293 cell line; patch clamp technique; transient receptor potential channel M2; Selectivity filter; Selectivity filter; Nematostella vectensis; nanodisc; Ag+ modification; structure of TRPM2 channel; quadruple residue motif},
	year = {2021},
	eissn = {2211-1247}
}

@article{MTMT:31941127,
	title = {Structural Pharmacology of TRP Channels},
	url = {https://m2.mtmt.hu/api/publication/31941127},
	author = {Zhao, Y. and McVeigh, B.M. and Moiseenkova-Bell, V.Y.},
	doi = {10.1016/j.jmb.2021.166914},
	journal-iso = {J MOL BIOL},
	journal = {JOURNAL OF MOLECULAR BIOLOGY},
	volume = {433},
	unique-id = {31941127},
	issn = {0022-2836},
	abstract = {Transient receptor potential (TRP) ion channels are a super-family of ion channels that mediate transmembrane cation flux with polymodal activation, ranging from chemical to physical stimuli. Furthermore, due to their ubiquitous expression and role in human diseases, they serve as potential pharmacological targets. Advances in cryo-EM TRP channel structural biology has revealed general, as well as diverse, architectural elements and regulatory sites among TRP channel subfamilies. Here, we review the endogenous and pharmacological ligand-binding sites of TRP channels and their regulatory mechanisms. © 2021 Elsevier Ltd},
	keywords = {ION CHANNELS; Structural biology; cryo-EM; TRP channel},
	year = {2021},
	eissn = {1089-8638}
}

@article{MTMT:31722651,
	title = {The structural basis for an on-off switch controlling Gβγ-mediated inhibition of TRPM3 channels},
	url = {https://m2.mtmt.hu/api/publication/31722651},
	author = {Behrendt, M. and Gruss, F. and Enzeroth, R. and Dembla, S. and Zhao, S. and Crassous, P.-A. and Mohr, F. and Nys, M. and Louros, N. and Gallardo, R. and Zorzini, V. and Wagner, D. and Economou, A. and Rousseau, F. and Schymkowitz, J. and Philipp, S.E. and Rohacs, T. and Ulens, C. and Oberwinkler, J.},
	doi = {10.1073/pnas.2001177117},
	journal-iso = {P NATL ACAD SCI USA},
	journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
	volume = {117},
	unique-id = {31722651},
	issn = {0027-8424},
	abstract = {TRPM3 channels play important roles in the detection of noxious heat and in inflammatory thermal hyperalgesia. The activity of these ion channels in somatosensory neurons is tightly regulated by μ-opioid receptors through the signaling of Gβγ proteins, thereby reducing TRPM3-mediated pain. We show here that Gβγ directly binds to a domain of 10 amino acids in TRPM3 and solve a cocrystal structure of this domain together with Gβγ. Using these data and mutational analysis of full-length proteins, we pinpoint three amino acids in TRPM3 and their interacting partners in Gβ1 that are individually necessary for TRPM3 inhibition by Gβγ. The 10-amino-acid Gβγ-interacting domain in TRPM3 is subject to alternative splicing. Its inclusion in or exclusion from TRPM3 channel proteins therefore provides a mechanism for switching on or off the inhibitory action that Gβγ proteins exert on TRPM3 channels. © 2020 National Academy of Sciences. All rights reserved.},
	keywords = {Alternative Splicing; TRP CHANNELS; GPCR signaling; OPIOID ANALGESIA},
	year = {2020},
	eissn = {1091-6490},
	pages = {29090-29100}
}

@article{MTMT:31718822,
	title = {Gating and calcium-sensing mechanisms of TRPA1 channels revealed},
	url = {https://m2.mtmt.hu/api/publication/31718822},
	author = {Brauchi, Sebastian E. and Rothberg, Brad S.},
	doi = {10.1016/j.ceca.2020.102278},
	journal-iso = {CELL CALCIUM},
	journal = {CELL CALCIUM},
	volume = {91},
	unique-id = {31718822},
	issn = {0143-4160},
	abstract = {Novel structures of the human TRPA1 channel were determined in the presence of the agonist iodoacetamide and the antagonist A-967079, to reveal the open and closed states of the channel, respectively. The structures further revealed the location of Ca2+ modulatory site that is likely conserved among several TRP subgroups.},
	keywords = {calcium; PAIN; CHANNEL; Sensory; TRP; Mustard},
	year = {2020},
	eissn = {1532-1991}
}

@article{MTMT:31366807,
	title = {Structural mechanisms of transient receptor potential ion channels},
	url = {https://m2.mtmt.hu/api/publication/31366807},
	author = {Cao, E.},
	doi = {10.1085/JGP.201811998},
	journal-iso = {J GEN PHYSIOL},
	journal = {JOURNAL OF GENERAL PHYSIOLOGY},
	volume = {152},
	unique-id = {31366807},
	issn = {0022-1295},
	abstract = {Transient receptor potential (TRP) ion channels are evolutionarily ancient sensory proteins that detect and integrate a wide range of physical and chemical stimuli. TRP channels are fundamental for numerous biological processes and are therefore associated with a multitude of inherited and acquired human disorders. In contrast to many other major ion channel families, high-resolution structures of TRP channels were not available before 2013. Remarkably, however, the subsequent “resolution revolution” in cryo-EM has led to an explosion of TRP structures in the last few years. These structures have confirmed that TRP channels assemble as tetramers and resemble voltage-gated ion channels in their overall architecture. But beyond the relatively conserved transmembrane core embedded within the lipid bilayer, each TRP subtype appears to be endowed with a unique set of soluble domains that may confer diverse regulatory mechanisms. Importantly, TRP channel structures have revealed sites and mechanisms of action of numerous synthetic and natural compounds, as well as those for endogenous ligands such as lipids, Ca2+, and calmodulin. Here, I discuss these recent findings with a particular focus on the conserved transmembrane region and how these structures may help to rationally target this important class of ion channels for the treatment of numerous human conditions. © 2020 Cao.},
	year = {2020},
	eissn = {1540-7748}
}

@article{MTMT:31697230,
	title = {Does Cyclic ADP-Ribose (cADPR) Activate the Non-selective Cation Channel TRPM2?},
	url = {https://m2.mtmt.hu/api/publication/31697230},
	author = {Fliegert, Ralf and Riekehr, Winnie M. and Guse, Andreas H.},
	doi = {10.3389/fimmu.2020.02018},
	journal-iso = {FRONT IMMUNOL},
	journal = {FRONTIERS IN IMMUNOLOGY},
	volume = {11},
	unique-id = {31697230},
	issn = {1664-3224},
	abstract = {TRPM2 is a non-selective, Ca2+-permeable cation channel widely expressed in immune cells. It is firmly established that the channel can be activated by intracellular adenosine 5 '-diphosphoribose (ADPR). Until recent cryo-EM structures have exhibited an additional nucleotide binding site in the N-terminus of the channel, this activation was thought to occur via binding to a C-terminal domain of the channel that is highly homologous to the ADPR pyrophosphatase NudT9. Over the years it has been controversially discussed whether the Ca(2+)mobilizing second messenger cyclic ADP ribose (cADPR) might also directly activate Ca(2+)entry via TRPM2. Here we will review the status of this discussion.},
	keywords = {calcium; signal transduction; ion channel; TRPM2; cADPR},
	year = {2020},
	eissn = {1664-3224}
}

@article{MTMT:31718821,
	title = {Phylogenetics Identifies Two Eumetazoan TRPM Clades and an Eighth TRP Family, TRP Soromelastatin (TRPS)},
	url = {https://m2.mtmt.hu/api/publication/31718821},
	author = {Himmel, Nathaniel J. and Gray, Thomas R. and Cox, Daniel N.},
	doi = {10.1093/molbev/msaa065},
	journal-iso = {MOL BIOL EVOL},
	journal = {MOLECULAR BIOLOGY AND EVOLUTION},
	volume = {37},
	unique-id = {31718821},
	issn = {0737-4038},
	abstract = {Transient receptor potential melastatins (TRPMs) are most well known as cold and menthol sensors, but are in fact broadly critical for life, from ion homeostasis to reproduction. Yet, the evolutionary relationship between TRPM channels remains largely unresolved, particularly with respect to the placement of several highly divergent members. To characterize the evolution of TRPM and like channels, we performed a large-scale phylogenetic analysis of >1,300 TRPM-like sequences from 14 phyla (Annelida, Arthropoda, Brachiopoda, Chordata, Cnidaria, Echinodermata, Hemichordata, Mollusca, Nematoda, Nemertea, Phoronida, Priapulida, Tardigrada, and Xenacoelomorpha), including sequences from a variety of recently sequenced genomes that fill what would otherwise be substantial taxonomic gaps. These findings suggest: 1) the previously recognized TRPM family is in fact two distinct families, including canonical TRPM channels and an eighth major previously undescribed family of animal TRP channel, TRP soromelastatin; 2) two TRPM clades predate the last bilaterian-cnidarian ancestor; and 3) the vertebrate-centric trend of categorizing TRPM channels as 1-8 is inappropriate for most phyla, including other chordates.},
	keywords = {Phylogenetics; transient receptor potential; TRPM; TRPs; Channel evolution; ced-11},
	year = {2020},
	eissn = {1537-1719},
	pages = {2034-2044}
}

@article{MTMT:31366806,
	title = {TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases},
	url = {https://m2.mtmt.hu/api/publication/31366806},
	author = {Hong, C. and Jeong, B. and Park, H.J. and Chung, J.Y. and Lee, J.E. and Kim, J. and Shin, Y.-C. and So, I.},
	doi = {10.3389/fphys.2020.00238},
	journal-iso = {FRONT PHYSIOL},
	journal = {FRONTIERS IN PHYSIOLOGY},
	volume = {11},
	unique-id = {31366806},
	abstract = {The development of treatment for neurodegenerative diseases (NDs) such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis is facing medical challenges due to the increasingly aging population. However, some pharmaceutical companies have ceased the development of therapeutics for NDs, and no new treatments for NDs have been established during the last decade. The relationship between ND pathogenesis and risk factors has not been completely elucidated. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where oxidative stress and disrupted Ca2+ homeostasis consequently lead to neuronal apoptosis. Reactive oxygen species (ROS) -sensitive TRP channels can be key risk factors as polymodal sensors, since progressive late onset with secondary pathological damage after initial toxic insult is one of the typical characteristics of NDs. Recent evidence indicates that the dysregulation of TRP channels is a missing link between disruption of Ca2+ homeostasis and neuronal loss in NDs. In this review, we discuss the latest findings regarding TRP channels to provide insights into the research and quests for alternative therapeutic candidates for NDs. As the structures of TRP channels have recently been revealed by cryo-electron microscopy, it is necessary to develop new TRP channel antagonists and reevaluate existing drugs. © Copyright © 2020 Hong, Jeong, Park, Chung, Lee, Kim, Shin and So.},
	keywords = {APOPTOSIS; CA2+; CAPSAZEPINE; VANILLOID RECEPTOR; Pathogenesis; review; human; Protein Transport; protein analysis; protein localization; nonhuman; nerve cell; sodium channel; protein phosphorylation; transient receptor potential channel; Cryoelectron Microscopy; PROTEIN FUNCTION; Tumor Necrosis Factor; Adenosine Triphosphate; molecular interaction; protein targeting; reactive oxygen metabolite; neurodegeneration; Parkinson disease; cell loss; protein modification; brain derived neurotrophic factor; potassium channel; ankyrin; vanilloid receptor 1; interleukin 1beta; Cell Death; Huntington chorea; 4 aminobutyric acid; degenerative disease; Alzheimer disease; membrane permeability; calcium homeostasis; amyotrophic lateral sclerosis; adenosine diphosphate ribose; amyloid beta protein; voltage gated calcium channel; PD; n methyl dextro aspartic acid; ROS; HD; transient receptor potential channel 6; AD; alpha amino 3 hydroxy 5 methyl 4 isoxazolepropionic acid; transient receptor potential channel 1; protein tyrosine kinase A; presenilin 1; neurotrophin receptor; transient receptor potential channel 7; transient receptor potential channel 5; transient receptor potential channel 4; transient receptor potential channel 3; transient receptor potential channel 2; TRP; polycystin; Oxidative stress},
	year = {2020},
	eissn = {1664-042X}
}

@article{MTMT:31042507,
	title = {A structural overview of the ion channels of the TRPM family},
	url = {https://m2.mtmt.hu/api/publication/31042507},
	author = {Huang, Yihe and Fliegert, Ralf and Guse, Andreas H. and Lu, Wei and Du, Juan},
	doi = {10.1016/j.ceca.2019.102111},
	journal-iso = {CELL CALCIUM},
	journal = {CELL CALCIUM},
	volume = {85},
	unique-id = {31042507},
	issn = {0143-4160},
	abstract = {The TRPM (transient receptor potential melastatin) family belongs to the superfamily of TRP cation channels. The TRPM subfamily is composed of eight members that are involved in diverse biological functions such as temperature sensing, inflammation, insulin secretion, and redox sensing. Since the first cloning of TRPM1 in 1998, tremendous progress has been made uncovering the function, structure, and pharmacology of this family. Complete structures of TRPM2, TRPM4, and TRPM8, as well as a partial structure of TRPM7, have been determined by cryo-EM, providing insights into their channel assembly, ion permeation, gating mechanisms, and structural pharmacology. Here we summarize the current knowledge about channel structure, emphasizing general features and principles of the structure of TRPM channels discovered since 2017. We also discuss some of the key unresolved issues in the field, including the molecular mechanisms underlying voltage and temperature dependence, as well as the functions of the TRPM channels' C-terminal domains.},
	keywords = {BINDING; IDENTIFICATION; ACTIVATION; PERMEATION; CRYSTAL-STRUCTURE; cation channel; structures; Pore; Cyclic ADP-Ribose; TRPM channels; ADENOSINE 5'-DIPHOSPHORIBOSE},
	year = {2020},
	eissn = {1532-1991}
}

@article{MTMT:31614855,
	title = {Global alignment and assessment of trp channel transmembrane domain structures to explore functional mechanisms},
	url = {https://m2.mtmt.hu/api/publication/31614855},
	author = {Huffer, K.E. and Aleksandrova, A.A. and Jara-Oseguera, A. and Forrest, L.R. and Swartz, K.J.},
	doi = {10.7554/eLife.58660},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {9},
	unique-id = {31614855},
	issn = {2050-084X},
	year = {2020},
	eissn = {2050-084X},
	pages = {1-33}
}

@article{MTMT:31697231,
	title = {Structure-Function Relationship of TRPM2: Recent Advances, Contradictions, and Open Questions},
	url = {https://m2.mtmt.hu/api/publication/31697231},
	author = {Kuehn, Frank J. P.},
	doi = {10.3390/ijms21186481},
	journal-iso = {INT J MOL SCI},
	journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
	volume = {21},
	unique-id = {31697231},
	issn = {1661-6596},
	abstract = {When in a particular scientific field, major progress is rapidly reached after a long period of relative stand-still, this is often achieved by the development or exploitation of new techniques and methods. A striking example is the new insights brought into the understanding of the gating mechanism of the transient receptor potential melastatin type 2 cation channel (TRPM2) by cryogenic electron microscopy structure analysis. When conventional methods are complemented by new ones, it is quite natural that established researchers are not fully familiar with the possibilities and limitations of the new method. On the other hand, newcomers may need some assistance in perceiving the previous knowledge in detail; they may not realize that some of their interpretations are at odds with previous results and need refinement. This may in turn trigger further studies with new and promising perspectives, combining the promises of several methodological approaches. With this review, I aim to give a comprehensive overview on functional data of several orthologous of TRPM2 that are nicely explained by structural studies. Moreover, I wish to point out some functional contradictions raised by the structural data. Finally, some open questions and some lines of possible future experimental approaches shall be discussed.},
	keywords = {transient receptor potential; cryogenic electron microscopy; adenosine diphospho ribose; NUDT9; ion channel orthologous},
	year = {2020},
	eissn = {1422-0067}
}

@article{MTMT:31366156,
	title = {The N-terminal domain in TRPM2 channel is a conserved nucleotide binding site},
	url = {https://m2.mtmt.hu/api/publication/31366156},
	author = {Lu, Wei and Du, Juan},
	doi = {10.1085/jgp.201912555},
	journal-iso = {J GEN PHYSIOL},
	journal = {JOURNAL OF GENERAL PHYSIOLOGY},
	volume = {152},
	unique-id = {31366156},
	issn = {0022-1295},
	year = {2020},
	eissn = {1540-7748}
}

@article{MTMT:31366805,
	title = {N-glycosylation state of TRPM8 protein revealed by terahertz spectroscopy and molecular modelling},
	url = {https://m2.mtmt.hu/api/publication/31366805},
	author = {Mernea, M. and Ulăreanu, R. and Călboreanu, O. and Chirițoiu, G. and Cucu, D. and Mihăilescu, D.F.},
	doi = {10.1016/j.bbagen.2020.129580},
	journal-iso = {BBA-GEN SUBJECTS},
	journal = {BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS},
	volume = {1864},
	unique-id = {31366805},
	issn = {0304-4165},
	abstract = {TRPM8 member of the TRP superfamily of membrane proteins participates to various cellular processes ranging from Ca2+ uptake and cold sensation to cellular proliferation and migration. TRPM8 is a large tetrameric protein with more than 70% of its residues located in the cytoplasm. TRPM8 is N-glycosylated, with a single site per subunit. This work focuses on the N-glycosylation of TRPM8 channel that was previously studied by our group in relation to proliferation and migration of tumoral cells. Here, experimental data performed with deglycosylating agents assess that the sole glycosylation site contains complex glycans with a molecular weight of 2.5 kDa. The glycosylation state of TRPM8 in cells untreated and treated with a deglycosylating agent was addressed with Terahertz (THz) spectroscopy. Results show a clear difference between cells comprising glycosylated and deglycosylated TRPM8, the first presenting an increased THz absorption. Human TRPM8 was modelled using as templates the available TRPM8 and other TRPM channels structures. Glycosylations were modelled by considering two glycan structures with molecular weight close to the experiment: shorter and branched at the first sugar unit (glc1) and longer and unbranched (glc2). Simulation of THz spectra based on the molecular dynamics of unglycosylated and the two glycosylated TRPM8 models in lipid membrane and solvation box showed that glycan structure strongly influences the THz spectrum of the channel and of other components from the simulation system. Only spectra of TRPM8 with glc1 glycans were in agreement with the experiment, leading to the validation of glc1 glycan structure. © 2020},
	keywords = {ABSORPTION; ARTICLE; protein determination; Molecular weight; priority journal; controlled study; glycan derivative; Experimental study; simulation; validation study; lipid membrane; molecular model; molecular dynamics; protein structure; SOLVATION; protein glycosylation; carbohydrate analysis; Terahertz spectroscopy; transient receptor potential channel M8; THz spectroscopy; TRPM8 N-glycosylation; TRPM8 structural model; TRPM8 structure},
	year = {2020},
	eissn = {1872-8006}
}

@article{MTMT:31042600,
	title = {The Journey to Discovering a Flatworm Target of Praziquantel: A Long TRP},
	url = {https://m2.mtmt.hu/api/publication/31042600},
	author = {Park, S.-K. and Marchant, J.S.},
	doi = {10.1016/j.pt.2019.11.002},
	journal-iso = {TRENDS PARASITOL},
	journal = {TRENDS IN PARASITOLOGY},
	volume = {36},
	unique-id = {31042600},
	issn = {1471-4922},
	year = {2020},
	eissn = {1471-5007},
	pages = {182-194}
}

@article{MTMT:31042601,
	title = {Transient receptor potential (TRP) channels: Biosensors for redox environmental stimuli and cellular status},
	url = {https://m2.mtmt.hu/api/publication/31042601},
	author = {Sakaguchi, R. and Mori, Y.},
	doi = {10.1016/j.freeradbiomed.2019.10.415},
	journal-iso = {FREE RADICAL BIO MED},
	journal = {FREE RADICAL BIOLOGY AND MEDICINE},
	volume = {146},
	unique-id = {31042601},
	issn = {0891-5849},
	year = {2020},
	eissn = {1873-4596},
	pages = {36-44}
}

@article{MTMT:31722650,
	title = {Ion channels as lipid sensors: from structures to mechanisms},
	url = {https://m2.mtmt.hu/api/publication/31722650},
	author = {Thompson, M.J. and Baenziger, J.E.},
	doi = {10.1038/s41589-020-00693-3},
	journal-iso = {NAT CHEM BIOL},
	journal = {NATURE CHEMICAL BIOLOGY},
	volume = {16},
	unique-id = {31722650},
	issn = {1552-4450},
	abstract = {Ion channels play critical roles in cellular function by facilitating the flow of ions across the membrane in response to chemical or mechanical stimuli. Ion channels operate in a lipid bilayer, which can modulate or define their function. Recent technical advancements have led to the solution of numerous ion channel structures solubilized in detergent and/or reconstituted into lipid bilayers, thus providing unprecedented insight into the mechanisms underlying ion channel–lipid interactions. Here, we describe how ion channel structures have evolved to respond to both lipid modulators and lipid activators to control the electrical activities of cells, highlighting diverse mechanisms and common themes. © 2020, Springer Nature America, Inc.},
	year = {2020},
	eissn = {1552-4469},
	pages = {1331-1342}
}

@article{MTMT:31365406,
	title = {Selective profiling of N- And C-terminal nucleotide-binding sites in a TRPM2 channel},
	url = {https://m2.mtmt.hu/api/publication/31365406},
	author = {Tóth, Balázs and Iordanov, Iordan and Csanády, László},
	doi = {10.1085/jgp.201912533},
	journal-iso = {J GEN PHYSIOL},
	journal = {JOURNAL OF GENERAL PHYSIOLOGY},
	volume = {152},
	unique-id = {31365406},
	issn = {0022-1295},
	abstract = {Transient receptor potential melastatin 2 (TRPM2) is a homotetrameric Ca2+-permeable cation channel important for the immune response, body temperature regulation, and insulin secretion, and is activated by cytosolic Ca2+ and ADP ribose (ADPR). ADPR binds to two distinct locations, formed by large N- and C-terminal cytosolic domains, respectively, of the channel protein. In invertebrate TRPM2 channels, the C-terminal site is not required for channel activity but acts as an active ADPR phosphohydrolase that cleaves the activating ligand. In vertebrate TRPM2 channels, the C-terminal site is catalytically inactive but cooperates with the N-terminal site in channel activation. The precise functional contributions to channel gating and the nucleotide selectivities of the two sites in various species have not yet been deciphered. For TRPM2 of the sea anemone Nematostella vectensis (nvTRPM2), catalytic activity is solely attributable to the C-terminal site. Here, we show that nvTRPM2 channel gating properties remain unaltered upon deletion of the C-terminal domain, indicating that the N-terminal site is single-handedly responsible for channel gating. Exploiting such functional independence of the N- and C-terminal sites, we selectively measure their affinity profiles for a series of ADPR analogues, as reflected by apparent affinities for channel activation and catalysis, respectively. Using site-directed mutagenesis, we confirm that the same N-terminal site observed in vertebrate TRPM2 channels was already present in ancient cnidarians. Finally, by characterizing the functional effects of six amino acid side chain truncations in the N-terminal site, we provide first insights into the mechanistic contributions of those side chains to TRPM2 channel gating. © 2020 Tóth et al. This article is distributed under the terms of an Attribution-Noncommercial-Share Alike-No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution-Noncommercial-Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).},
	year = {2020},
	eissn = {1540-7748},
	orcid-numbers = {Tóth, Balázs/0000-0002-1257-2597; Iordanov, Iordan/0000-0001-8251-5857; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:31366809,
	title = {TRPM2, linking oxidative stress and Ca2+ permeation to NLRP3 inflammasome activation},
	url = {https://m2.mtmt.hu/api/publication/31366809},
	author = {Wang, L. and Negro, R. and Wu, H.},
	doi = {10.1016/j.coi.2020.01.005},
	journal-iso = {CURR OPIN IMMUNOL},
	journal = {CURRENT OPINION IN IMMUNOLOGY},
	volume = {62},
	unique-id = {31366809},
	issn = {0952-7915},
	abstract = {The NLRP3 inflammasome is an innate immune platform that senses various pathogens and sterile insults. NLRP3 stimulation leads to activation of caspase-1, the secretion of pro-inflammatory cytokines and an inflammatory cell death called pyroptosis. Effectors of the NLRP3 inflammasome efficiently drive an immune response, not only providing protection in physiological settings but also promoting pathology when over activated. Generation of reactive oxygen species (ROS) and intracellular calcium mobilization can activate the NLRP3 inflammasome. Recent studies suggest that TRPM2 is a calcium-permeable cation channel mediating ROS-dependent NLRP3 activation. Here, we review the role of TRPM2 in NLRP3 inflammasome activation and provide an update on new functional and structural discoveries. Understanding the molecular mechanism of TRPM2 dependent NLRP3 inflammasome activation will shed lights on this complex pathway and help the developing of therapeutic strategies. © 2020 Elsevier Ltd},
	keywords = {cytokine; review; human; innate immunity; Calcium ion; enzyme activation; POSITIVE FEEDBACK; PROTEIN FUNCTION; upregulation; immunoglobulin enhancer binding protein; cytokine release; calcium transport; interleukin 1beta converting enzyme; cryopyrin; Pyroptosis; clusterin; TLR signaling; Oxidative stress},
	year = {2020},
	eissn = {1879-0372},
	pages = {131-135}
}

@article{MTMT:31366808,
	title = {Lipid Interactions of a Ciliary Membrane TRP Channel: Simulation and Structural Studies of Polycystin-2},
	url = {https://m2.mtmt.hu/api/publication/31366808},
	author = {Wang, Q. and Corey, R.A. and Hedger, G. and Aryal, P. and Grieben, M. and Nasrallah, C. and Baronina, A. and Pike, A.C.W. and Shi, J. and Carpenter, E.P. and Sansom, M.S.P.},
	doi = {10.1016/j.str.2019.11.005},
	journal-iso = {STRUCTURE},
	journal = {STRUCTURE},
	volume = {28},
	unique-id = {31366808},
	issn = {0969-2126},
	abstract = {Polycystin-2 (PC2) is a transient receptor potential (TRP) channel present in ciliary membranes of the kidney. PC2 shares a transmembrane fold with other TRP channels, in addition to an extracellular domain found in TRPP and TRPML channels. Using molecular dynamics (MD) simulations and cryoelectron microscopy we identify and characterize PIP2 and cholesterol interactions with PC2. PC2 is revealed to have a PIP binding site close to the equivalent vanilloid/lipid binding site in the TRPV1 channel. A 3.0-Å structure reveals a binding site for cholesterol on PC2. Cholesterol interactions with the channel at this site are characterized by MD simulations. The two classes of lipid binding sites are compared with sites observed in other TRPs and in Kv channels. These findings suggest PC2, in common with other ion channels, may be modulated by both PIPs and cholesterol, and position PC2 within an emerging model of the roles of lipids in the regulation and organization of ciliary membranes. © 2019 The Authors Wang et al. use molecular dynamics simulations and cryoelectron microscopy to explore interactions of the PC2 channel with lipids. Phosphatidylinositol phosphates (PIPs) bind to a site corresponding to the vanilloid/lipid binding site of TRPV1, whereas cholesterol binds to a different site. This suggests PC2 may be modulated by PIPs and cholesterol. © 2019 The Authors},
	keywords = {ARTICLE; LIPIDS; human; priority journal; controlled study; regulatory mechanism; Protein Binding; Protein Folding; Cryoelectron Microscopy; Cryoelectron Microscopy; cholesterol; lipid bilayer; Phospholipid bilayer; lipid composition; phospholipid; molecular dynamics; molecular dynamics; protein structure; hydrogen bond; protein interaction; primary cilium; lipid binding protein; TRP channel; polycystin-2; phosphatidylinositol bisphosphate; polycystin 2},
	year = {2020},
	eissn = {1878-4186},
	pages = {169-184.e5}
}

@article{MTMT:31366811,
	title = {Structure and function of the calcium-selective TRP channel TRPV6},
	url = {https://m2.mtmt.hu/api/publication/31366811},
	author = {Yelshanskaya, M.V. and Nadezhdin, K.D. and Kurnikova, M.G. and Sobolevsky, A.I.},
	doi = {10.1113/JP279024},
	journal-iso = {J PHYSIOL-LONDON},
	journal = {JOURNAL OF PHYSIOLOGY-LONDON},
	volume = {in press},
	unique-id = {31366811},
	issn = {0022-3751},
	keywords = {calcium; LIPIDS; ION CHANNELS; X-RAY CRYSTALLOGRAPHY; structure; TRP CHANNELS; gating; cryo-EM},
	year = {2020},
	eissn = {1469-7793},
	pages = {2020.02.19}
}

@article{MTMT:31366810,
	title = {Current View of Ligand and Lipid Recognition by the Menthol Receptor TRPM8},
	url = {https://m2.mtmt.hu/api/publication/31366810},
	author = {Yin, Y. and Lee, S.-Y.},
	doi = {10.1016/j.tibs.2020.05.008},
	journal-iso = {TRENDS BIOCHEM SCI},
	journal = {TRENDS IN BIOCHEMICAL SCIENCES},
	volume = {45},
	unique-id = {31366810},
	issn = {0968-0004},
	keywords = {transient receptor potential ion channels; COLD RECEPTOR; allosteric coupling; cooling agent; menthol receptor; PI(4,5)P2 regulation},
	year = {2020},
	eissn = {1362-4326},
	pages = {806-819}
}

@article{MTMT:31647884,
	title = {Roles of NAD+ and its metabolites regulated calcium channels in cancer},
	url = {https://m2.mtmt.hu/api/publication/31647884},
	author = {Yu, Peilin and Cai, Xiaobo and Liang, Yan and Wang, Mingxiang and Yang, Wei},
	doi = {10.3390/molecules25204826},
	journal-iso = {MOLECULES},
	journal = {MOLECULES},
	volume = {25},
	unique-id = {31647884},
	issn = {1420-3049},
	abstract = {Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor for redox enzymes, but also moonlights as a regulator for ion channels, the same as its metabolites. Ca2+ homeostasis is dysregulated in cancer cells and affects processes such as tumorigenesis, angiogenesis, autophagy, progression, and metastasis. Herein, we summarize the regulation of the most common calcium channels (TRPM2, TPCs, RyRs, and TRPML1) by NAD+ and its metabolites, with a particular focus on their roles in cancers. Although the mechanisms of NAD+ metabolites in these pathological processes are yet to be clearly elucidated, these ion channels are emerging as potential candidates of alternative targets for anticancer therapy. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.},
	keywords = {METABOLITES; CANCER; CALCIUM CHANNELS; NAD+},
	year = {2020},
	eissn = {1420-3049}
}

@article{MTMT:31721987,
	title = {Medicinal chemistry perspective of TRPM2 channel inhibitors: where we are and where we might be heading?},
	url = {https://m2.mtmt.hu/api/publication/31721987},
	author = {Zhang, H. and Zhao, S. and Yu, J. and Yang, W. and Liu, Z. and Zhang, L.},
	doi = {10.1016/j.drudis.2020.09.039},
	journal-iso = {DRUG DISCOV TODAY},
	journal = {DRUG DISCOVERY TODAY},
	volume = {25},
	unique-id = {31721987},
	issn = {1359-6446},
	abstract = {Transient receptor potential melastatin 2 (TRPM2) is a Ca2+- permeable nonselective cation channel that is involved in diverse biological functions as a cellular sensor for oxidative stress and temperature. It has been considered a promising therapeutic target for the treatment of ischemia/reperfusion (IR) injury, inflammation, cancer, and neurodegenerative diseases. Development of highly potent and selective TRPM2 inhibitors and validation of their use in relevant disease models will advance drug discovery. In this review, we describe the molecular structures and gating mechanism of the TRPM2 channel, and offer a comprehensive review of advances in the discovery of TRPM2 inhibitors. Furthermore, we analyze the properties of reported TRPM2 inhibitors with an emphasis on how specific inhibitors targeting this channel could be better developed. © 2020 Elsevier Ltd},
	year = {2020},
	eissn = {1878-5832},
	pages = {2326-2334}
}

@article{MTMT:31509384,
	title = {Irritant-evoked activation and calcium modulation of the TRPA1 receptor},
	url = {https://m2.mtmt.hu/api/publication/31509384},
	author = {Zhao, Jianhua and King, John V. Lin and Paulsen, Candice E. and Cheng, Yifan and Julius, David},
	doi = {10.1038/s41586-020-2480-9},
	journal-iso = {NATURE},
	journal = {NATURE},
	unique-id = {31509384},
	issn = {0028-0836},
	abstract = {The transient receptor potential ion channel TRPA1 is expressed by primary afferent nerve fibres, in which it functions as a low-threshold sensor for structurally diverse electrophilic irritants, including small volatile environmental toxicants and endogenous algogenic lipids(1). TRPA1 is also a 'receptor-operated' channel whose activation downstream of metabotropic receptors elicits inflammatory pain or itch, making it an attractive target for novel analgesic therapies(2). However, the mechanisms by which TRPA1 recognizes and responds to electrophiles or cytoplasmic second messengers remain unknown. Here we use strutural studies and electrophysiology to show that electrophiles act through a two-step process in which modification of a highly reactive cysteine residue (C621) promotes reorientation of a cytoplasmic loop to enhance nucleophilicity and modification of a nearby cysteine (C665), thereby stabilizing the loop in an activating configuration. These actions modulate two restrictions controlling ion permeation, including widening of the selectivity filter to enhance calcium permeability and opening of a canonical gate at the cytoplasmic end of the pore. We propose a model to explain functional coupling between electrophile action and these control points. We also characterize a calcium-binding pocket that is highly conserved across TRP channel subtypes and accounts for all aspects of calcium-dependent TRPA1 regulation, including potentiation, desensitization and activation by metabotropic receptors. These findings provide a structural framework for understanding how a broad-spectrum irritant receptor is controlled by endogenous and exogenous agents that elicit or exacerbate pain and itch.},
	year = {2020},
	eissn = {1476-4687},
	orcid-numbers = {Zhao, Jianhua/0000-0002-4997-766X; Cheng, Yifan/0000-0001-9535-0369}
}

@article{MTMT:30658837,
	title = {Synthesis of terminal ribose analogues of adenosine 5'-diphosphate ribose (ADPR) as probes for the Transient Receptor Potential (TRP) cation channel TRPM2.},
	url = {https://m2.mtmt.hu/api/publication/30658837},
	author = {Baszczyňski, Ondrej and Watt, Joanna M and Rozewitz, Monika D and Guse, Andreas H and Fliegert, Ralf and Potter, Barry V L},
	doi = {10.1021/acs.joc.9b00338},
	journal-iso = {J ORG CHEM},
	journal = {JOURNAL OF ORGANIC CHEMISTRY},
	volume = {84},
	unique-id = {30658837},
	issn = {0022-3263},
	abstract = {TRPM2 (transient receptor potential cation channel, subfamily M, member 2) is a non-selective cation channel involved in the response to oxidative stress and in inflammation. Its role in autoimmune and neurodegenerative diseases makes it an attractive pharmacological target. Binding of the nucleotide adenosine 5'-diphosphate ribose (ADPR) to the cytosolic NUDT9 homology (NUDT9H) domain activates the channel. A detailed understanding of how ADPR interacts with the TRPM2 ligand binding domain is lacking, hampering the rational design of modulators, but the terminal ribose of ADPR is known to be essential for activation. To study its role in more detail we designed synthetic routes to novel analogues of ADPR and 2'-deoxy-ADPR that were modified only by removal of a single hydroxyl group from of the terminal ribose. The ADPR analogues were obtained by coupling nucleoside phosphorimidazolides to deoxysugar phosphates. The corresponding C2″-based analogues proved to be unstable. The C1″- and C3″-ADPR analogues were evaluated electrophysiologically by patch-clamp in TRPM2-expressing HEK293 cells. In addition, a compound with all hydroxyl groups of the terminal ribose blocked as its 1"-α-methylfuranoside-2", 3"-isopropylidene derivative was evaluated. Removal of either C1" or C3" hydroxyl groups from ADPR resulted in loss of agonist activity. Both these modifications, and blocking all three hydroxyl groups resulted in ADPR antagonists. Our results demonstrate the critical role of these hydroxyl groups in channel activation.},
	year = {2019},
	eissn = {1520-6904},
	pages = {6143-6157}
}

@article{MTMT:30766409,
	title = {Transient receptor potential channels in the context of nociception and pain - recent insights into TRPM3 properties and function},
	url = {https://m2.mtmt.hu/api/publication/30766409},
	author = {Behrendt, Marc},
	doi = {10.1515/hsz-2018-0455},
	journal-iso = {BIOL CHEM},
	journal = {BIOLOGICAL CHEMISTRY},
	volume = {400},
	unique-id = {30766409},
	issn = {1431-6730},
	abstract = {Potential harmful stimuli like heat, mechanical pressure or chemicals are detected by specialized cutaneous nerve fiber endings of nociceptor neurons in a process called nociception. Acute stimulation results in immediate protective reflexes and pain sensation as a normal, physiological behavior. However, ongoing (chronic) pain is a severe pathophysiological condition with diverse pathogeneses that is clinically challenging because of limited therapeutic options. Therefore, an urgent need exists for new potent and specific analgesics without afflicting adverse effects. Recently, TRPM3, a member of the superfamily of transient receptor potential (TRP) ion channels, has been shown to be expressed in nociceptors and to be involved in the detection of noxious heat (acute pain) as well as inflammatory hyperalgesia (acute and chronic pain). Current results in TRPM3 research indicate that this ion channel might not only be part of yet unraveled mechanisms underlying chronic pain but also has the potential to become a clinically relevant pharmacological target of future analgesic strategies. The aim of this review is to summarize and present the basic features of TRPM3 proteins and channels, to highlight recent findings and developments and to provide an outlook on emerging directions of TRPM3 research in the field of chronic pain.},
	keywords = {HEAT; HYPERALGESIA; ANALGESIA; G-protein coupled receptors; TRP ion channels; opiods},
	year = {2019},
	eissn = {1437-4315},
	pages = {917-926}
}

@article{MTMT:31042606,
	title = {Emerging structural biology of TRPM subfamily channels},
	url = {https://m2.mtmt.hu/api/publication/31042606},
	author = {Chen, Y. and Zhang, X. and Yang, T. and Bi, R. and Huang, Z. and Ding, H. and Li, J. and Zhang, J.},
	doi = {10.1016/j.ceca.2019.02.011},
	journal-iso = {CELL CALCIUM},
	journal = {CELL CALCIUM},
	volume = {79},
	unique-id = {31042606},
	issn = {0143-4160},
	year = {2019},
	eissn = {1532-1991},
	pages = {75-79}
}

@article{MTMT:30870285,
	title = {Structural insights into TRPM8 inhibition and desensitization},
	url = {https://m2.mtmt.hu/api/publication/30870285},
	author = {Diver, Melinda M. and Cheng, Yifan and Julius, David},
	doi = {10.1126/science.aax6672},
	journal-iso = {SCIENCE},
	journal = {SCIENCE},
	volume = {365},
	unique-id = {30870285},
	issn = {0036-8075},
	abstract = {The transient receptor potential melastatin 8 (TRPM8) ion channel is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we present cryo-electron microscopy structures of TRPM8 in ligand-free, antagonist-bound, or calcium-bound forms, revealing how robust conformational changes give rise to two nonconducting states, closed and desensitized. We describe a malleable ligand-binding pocket that accommodates drugs of diverse chemical structures, and we delineate the ion permeation pathway, including the contribution of lipids to pore architecture. Furthermore. we show that direct calcium binding mediates stimulus-evoked desensitization, clarifying this important mechanism of sensory adaptation. We observe large rearrangements within the S4-S5 linker that reposition the S1-S4 and pore domains relative to the TRP helix, leading us to propose a distinct model for modulation of TRPM8 and possibly other TRP channels.},
	year = {2019},
	eissn = {1095-9203},
	pages = {1434-+},
	orcid-numbers = {Cheng, Yifan/0000-0001-9535-0369}
}

@article{MTMT:30870287,
	title = {Cryo-EM structure of TRPC5 at 2.8-angstrom resolution reveals unique and conserved structural elements essential for channel function},
	url = {https://m2.mtmt.hu/api/publication/30870287},
	author = {Duan, Jingjing and Li, Jian and Chen, Gui-Lan and Ge, Yan and Liu, Jieyu and Xie, Kechen and Peng, Xiaogang and Zhou, Wei and Zhong, Jianing and Zhang, Yixing and Xu, Jie and Xue, Changhu and Liang, Bo and Zhu, Lan and Liu, Wei and Zhang, Cheng and Tian, Xiao-Li and Wang, Jianbin and Clapham, David E. and Zeng, Bo and Li, Zongli and Zhang, Jin},
	doi = {10.1126/sciadv.aaw7935},
	journal-iso = {SCI ADV},
	journal = {SCIENCE ADVANCES},
	volume = {5},
	unique-id = {30870287},
	issn = {2375-2548},
	abstract = {The transient receptor potential canonical subfamily member 5 (TRPC5), one of seven mammalian TRPC members, is a nonselective calcium-permeant cation channel. TRPC5 is of considerable interest as a drug target in the treatment of progressive kidney disease, depression, and anxiety. Here, we present the 2.8-angstrom resolution cryo-electron microscopy (cryo-EM) structure of the mouse TRPC5 (mTRPC5) homotetramer. Comparison of the TRPC5 structure to previously determined structures of other TRPC and TRP channels reveals differences in the extracellular pore domain and in the length of the S3 helix. The disulfide bond at the extracellular side of the pore and a preceding small loop are essential elements for its proper function. This high-resolution structure of mTRPC5, combined with electrophysiology and mutagenesis, provides insight into the lipid modulation and gating mechanisms of the TRPC family of ion channels.},
	year = {2019},
	eissn = {2375-2548},
	orcid-numbers = {Duan, Jingjing/0000-0003-2716-2627; Zhong, Jianing/0000-0002-2781-3437; Liang, Bo/0000-0002-5617-9228}
}

@article{MTMT:30746777,
	title = {TRP ion channels: Proteins with conformational flexibility},
	url = {https://m2.mtmt.hu/api/publication/30746777},
	author = {Elena Lopez-Romero, Ana and Hernandez-Araiza, Ileana and Torres-Quiroz, Francisco and Tovar-Y-Romo, Luis B. and Islas, Leon D. and Rosenbaum, Tamara},
	doi = {10.1080/19336950.2019.1626793},
	journal-iso = {CHANNELS},
	journal = {CHANNELS},
	volume = {13},
	unique-id = {30746777},
	issn = {1933-6950},
	abstract = {Ion channels display conformational changes in response to binding of their agonists and antagonists. The study of the relationships between the structure and the function of these proteins has witnessed considerable advances in the last two decades using a combination of techniques, which include electrophysiology, optical approaches (i.e. patch clamp fluorometry, incorporation of non-canonic amino acids, etc.), molecular biology (mutations in different regions of ion channels to determine their role in function) and those that have permitted the resolution of their structures in detail (X-ray crystallography and cryo-electron microscopy). The possibility of making correlations among structural components and functional traits in ion channels has allowed for more refined conclusions on how these proteins work at the molecular level. With the cloning and description of the family of Transient Receptor Potential (TRP) channels, our understanding of several sensory-related processes has also greatly moved forward. The response of these proteins to several agonists, their regulation by signaling pathways as well as by protein-protein and lipid-protein interactions and, in some cases, their biophysical characteristics have been studied thoroughly and, recently, with the resolution of their structures, the field has experienced a new boom. This review article focuses on the conformational changes in the pores, concentrating on some members of the TRP family of ion channels (TRPV and TRPA subfamilies) that result in changes in their single-channel conductances, a phenomenon that may lead to fine-tuning the electrical response to a given agonist in a cell.},
	keywords = {ION CHANNELS; LIPID-PROTEIN INTERACTIONS; structure-function; TRP CHANNELS},
	year = {2019},
	eissn = {1933-6969},
	pages = {207-226},
	orcid-numbers = {Rosenbaum, Tamara/0000-0002-4791-3195}
}

@article{MTMT:30642658,
	title = {Multiscale Simulations of Biological Membranes: The Challenge To Understand Biological Phenomena in a Living Substance},
	url = {https://m2.mtmt.hu/api/publication/30642658},
	author = {Enkavi, Giray and Javanainen, Matti and Kulig, Waldemar and Róg, Tomasz and Vattulainen, Ilpo},
	doi = {10.1021/acs.chemrev.8b00538},
	journal-iso = {CHEM REV},
	journal = {CHEMICAL REVIEWS},
	volume = {119},
	unique-id = {30642658},
	issn = {0009-2665},
	year = {2019},
	eissn = {1520-6890},
	pages = {5607-5774}
}

@article{MTMT:31042605,
	title = {Pharmacology of JNJ-28583113: A novel TRPM2 antagonist},
	url = {https://m2.mtmt.hu/api/publication/31042605},
	author = {Fourgeaud, L. and Dvorak, C. and Faouzi, M. and Starkus, J. and Sahdeo, S. and Wang, Q. and Lord, B. and Coate, H. and Taylor, N. and He, Y. and Qin, N. and Wickenden, A. and Carruthers, N. and Lovenberg, T.W. and Penner, R. and Bhattacharya, A.},
	doi = {10.1016/j.ejphar.2019.03.043},
	journal-iso = {EUR J PHARMACOL},
	journal = {EUROPEAN JOURNAL OF PHARMACOLOGY},
	volume = {853},
	unique-id = {31042605},
	issn = {0014-2999},
	year = {2019},
	eissn = {1879-0712},
	pages = {299-307}
}

@article{MTMT:31042607,
	title = {What is new about mild temperature sensing? A review of recent findings},
	url = {https://m2.mtmt.hu/api/publication/31042607},
	author = {García-Ávila, M. and Islas, L.D.},
	doi = {10.1080/23328940.2019.1607490},
	journal-iso = {TEMPERATURE},
	journal = {TEMPERATURE},
	volume = {6},
	unique-id = {31042607},
	issn = {2332-8940},
	year = {2019},
	eissn = {2332-8959},
	pages = {132-141}
}

@article{MTMT:30766413,
	title = {Novel CaM-binding motif in its NudT9H domain contributes to temperature sensitivity of TRPM2},
	url = {https://m2.mtmt.hu/api/publication/30766413},
	author = {Gattkowski, Ellen and Johnsen, Anke and Bauche, Andreas and Moeckl, Franziska and Kulow, Frederike and Alai, Maria Garcia and Rutherford, Trevor J. and Fliegert, Ralf and Tidow, Henning},
	doi = {10.1016/j.bbamcr.2018.12.010},
	journal-iso = {BBA-MOL CELL RES},
	journal = {BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH},
	volume = {1866},
	unique-id = {30766413},
	issn = {0167-4889},
	abstract = {TRPM2 is a non-selective, Ca2+-permeable cation channel, which plays a role in cell death but also contributes to diverse immune cell functions. In addition, TRPM2 contributes to the control of body temperature and is involved in perception of non-noxious heat and thermotaxis. TRPM2 is regulated by many factors including Ca2+, ADPR, 2'-deoxy-ADPR, Ca2+-CaM, and temperature. However, the molecular basis for the temperature sensitivity of TRPM2 as well as the interplay between the regulatory factors is still not understood.Here we identify a novel CaM-binding site in the unique NudT9H domain of TRPM2. Using a multipronged biophysical approach we show that binding of Ca2+-CaM to this site occurs upon partial unfolding at temperatures > 35 degrees C and prevents further thermal destabilization. In combination with patch-clamp measurements of full-length TRPM2 our results suggest a role of this CaM-binding site in the temperature sensitivity of TRPM2.This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech},
	keywords = {calcium channel; CALMODULIN-BINDING; TRPM2; Temperature sensor; 2 '-deoxy-ADPR},
	year = {2019},
	eissn = {1879-2596},
	pages = {1162-1170}
}

@article{MTMT:30870275,
	title = {Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel},
	url = {https://m2.mtmt.hu/api/publication/30870275},
	author = {Huang, Yihe and Roth, Becca and Lu, Wei and Du, Juan},
	doi = {10.7554/eLife.50175},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {8},
	unique-id = {30870275},
	issn = {2050-084X},
	abstract = {TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca2+ and ADP ribose (ADPR), an NAD(+)-metabolite produced under oxidative stress and neurodegenerative conditions, suggests a role in neurological disorders. We provide a central concept between triple-site ligand binding and the channel gating of human TRPM2. We show consecutive structural rearrangements and channel activation of TRPM2 induced by binding of ADPR in two indispensable locations, and the binding of Ca2+ in the transmembrane domain. The 8-Br-cADPR-an antagonist of cADPR-binds only to the MHR1/2 domain and inhibits TRPM2 by stabilizing the channel in an apo-like conformation. We conclude that MHR1/2 acts as a orthostatic ligand-binding site for TRPM2. The NUDT9-H domain binds to a second ADPR to assist channel activation in vertebrates, but not necessary in invertebrates. Our work provides insights into the gating mechanism of human TRPM2 and its pharmacology.},
	year = {2019},
	eissn = {2050-084X},
	orcid-numbers = {Lu, Wei/0000-0002-3009-1025}
}

@article{MTMT:30637149,
	title = {Enzyme activity and selectivity filter stability of ancient TRPM2 channels were simultaneously lost in early vertebrates},
	url = {https://m2.mtmt.hu/api/publication/30637149},
	author = {Iordanov, Iordan and Tóth, Balázs and Szöllősi, András and Csanády, László},
	doi = {10.7554/eLife.44556},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {8},
	unique-id = {30637149},
	issn = {2050-084X},
	abstract = {Transient Receptor Potential Melastatin 2 (TRPM2) is a cation channel important for the immune response, insulin secretion, and body temperature regulation. It is activated by cytosolic ADP ribose (ADPR) and contains a nudix-type motif 9 (NUDT9)-homology (NUDT9-H) domain homologous to ADPR phosphohydrolases (ADPRases). Human TRPM2 (hsTRPM2) is catalytically inactive due to mutations in the conserved Nudix box sequence. Here, we show that TRPM2 Nudix motifs are canonical in all invertebrates but vestigial in vertebrates. Correspondingly, TRPM2 of the cnidarian Nematostella vectensis (nvTRPM2) and the choanoflagellate Salpingoeca rosetta (srTRPM2) are active ADPRases. Disruption of ADPRase activity fails to affect nvTRPM2 channel currents, reporting a catalytic cycle uncoupled from gating. Furthermore, pore sequence substitutions responsible for inactivation of hsTRPM2 also appeared in vertebrates. Correspondingly, zebrafish (Danio rerio) TRPM2 (drTRPM2) and hsTRPM2 channels inactivate, but srTRPM2 and nvTRPM2 currents are stable. Thus, catalysis and pore stability were lost simultaneously in vertebrate TRPM2 channels.},
	keywords = {Xenopus; E. coli; molecular biophysics; Structural biology; Selectivity filter; ADP ribose; Nudix hydrolase; channel enzyme; rundown},
	year = {2019},
	eissn = {2050-084X},
	orcid-numbers = {Iordanov, Iordan/0000-0001-8251-5857; Tóth, Balázs/0000-0002-1257-2597; Szöllősi, András/0000-0002-5570-4609; Csanády, László/0000-0002-6547-5889}
}

@article{MTMT:31042517,
	title = {The ion selectivity filter is not an activation gate in TRPV1-3 channels},
	url = {https://m2.mtmt.hu/api/publication/31042517},
	author = {Jara-Oseguera, A. and Huffer, K.E. and Swartz, K.J.},
	doi = {10.7554/eLife.51212},
	journal-iso = {ELIFE},
	journal = {ELIFE},
	volume = {8},
	unique-id = {31042517},
	issn = {2050-084X},
	year = {2019},
	eissn = {2050-084X}
}

@article{MTMT:31042589,
	title = {Functional importance of NUDT9H domain and N-terminal ADPR-binding pocket in two species variants of vertebrate TRPM2 channels},
	url = {https://m2.mtmt.hu/api/publication/31042589},
	author = {Kuehn, Frank J. P. and Ehrlich, Wiebke and Barth, Daniel and Kuehn, Cornelia and Lueckhoff, Andreas},
	doi = {10.1038/s41598-019-55232-5},
	journal-iso = {SCI REP},
	journal = {SCIENTIFIC REPORTS},
	volume = {9},
	unique-id = {31042589},
	issn = {2045-2322},
	abstract = {There are at least two different principles of how ADP-ribose (ADPR) induces activation of TRPM2 channels. In human TRPM2, gating requires the C-terminal NUDT9H domain as ADPR-binding module, whereas in sea anemone, NUDT9H is dispensable and binding of ADPR occurs N-terminally. Zebrafish TRPM2 needs both, the N-terminal ADPR-binding pocket and NUDT9H. Our aim was to pinpoint the relative functional contributions of NUDT9H and the N-terminal ADPR-binding pocket in zebrafish TRPM2, to identify fundamental mechanisms of ADPR-directed gating. We show that the NUDT9H domains of human and zebrafish TRPM2 are interchangeable since chimeras generate ADPR-sensitive channels. A point mutation at a highly conserved position within NUDT9H induces loss-of-function in both vertebrate channels. The substrate specificity of zebrafish TRPM2 corresponds to that of sea anemone TRPM2, indicating gating by the proposed N-terminal ADPR-binding pocket. However, a point mutation in this region abolishes ADPR activation also in human TRPM2. These findings provide functional evidence for an uniform N-terminal ADPR-binding pocket in TRPM2 of zebrafish and sea anemone with modified function in human TRPM2. The structural importance of NUDT9H in vertebrate TRPM2 can be associated with a single amino acid residue which is not directly involved in the binding of ADPR.},
	keywords = {ribose; ADENOSINE 5'-DIPHOSPHORIBOSE},
	year = {2019},
	eissn = {2045-2322}
}

@article{MTMT:30628107,
	title = {Different substrate specificities of the two ADPR binding sites in TRPM2 channels of Nematostella vectensis and the role of IDPR.},
	url = {https://m2.mtmt.hu/api/publication/30628107},
	author = {Kühn, Frank J P and Watt, Joanna M and Potter, Barry V L and Lückhoff, Andreas},
	doi = {10.1038/s41598-019-41531-4},
	journal-iso = {SCI REP},
	journal = {SCIENTIFIC REPORTS},
	volume = {9},
	unique-id = {30628107},
	issn = {2045-2322},
	abstract = {NvTRPM2 (Nematostella vectensis Transient Receptor Potential Melastatin 2), the species variant of the human apoptosis-related cation channel hTRPM2, is gated by ADP-ribose (ADPR) independently of the C-terminal NUDT9H domain that mediates ADPR-directed gating in hTRPM2. The decisive binding site in NvTRPM2 is likely to be identical with the N-terminal ADPR binding pocket in zebra fish DrTRPM2. Our aim was a characterization of this binding site in NvTRPM2 with respect to its substrate specificity, in comparison to the classical ADPR interaction site within NUDT9H that is highly homologous in hTRPM2 and NvTRPM2, although only in NvTRPM2, catalytic (ADPRase) activity is conserved. With various ADPR analogues, key differences of the two sites were identified. Particularly, two reported antagonists on hTRPM2 were agonists on NvTRPM2. Moreover, IDP-ribose (IDPR) induced currents both in hTRPM2 and NvTRPM2 but not in NvTRPM2 mutants in which NUDT9H was absent. Thus, IDPR acts on NUDT9H rather than N-terminally, revealing a regulatory function of NUDT9H in NvTRPM2 opposed to that in hTRPM2. We propose that IDPR competitively inhibits the ADPRase function of NUDT9H and evokes ADPR accumulation. The findings provide important insights into the structure-function relationship of NvTRPM2 and will allow further characterization of the novel ADPR interaction site.},
	year = {2019},
	eissn = {2045-2322}
}

@article{MTMT:31042602,
	title = {Interfacial Binding Sites for Cholesterol on TRP Ion Channels},
	url = {https://m2.mtmt.hu/api/publication/31042602},
	author = {Lee, A.G.},
	doi = {10.1016/j.bpj.2019.10.011},
	journal-iso = {BIOPHYS J},
	journal = {BIOPHYSICAL JOURNAL},
	volume = {117},
	unique-id = {31042602},
	issn = {0006-3495},
	year = {2019},
	eissn = {1542-0086},
	pages = {2020-2033}
}

@article{MTMT:31042609,
	title = {Activated NLR family pyrin domain containing 3 (NLRP3) inflammasome in keratinocytes promotes cutaneous T-cell response in patients with vitiligo},
	url = {https://m2.mtmt.hu/api/publication/31042609},
	author = {Li, S. and Kang, P. and Zhang, W. and Jian, Z. and Zhang, Q. and Yi, X. and Guo, S. and Guo, W. and Shi, Q. and Li, B. and He, Y. and Song, P. and Liu, L. and Li, K. and Wang, G. and Gao, T. and Li, C.},
	doi = {10.1016/j.jaci.2019.10.036},
	journal-iso = {J ALLERGY CLIN IMMUN},
	journal = {JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY},
	volume = {2019},
	unique-id = {31042609},
	issn = {0091-6749},
	year = {2019},
	eissn = {1097-6825},
	pages = {In press}
}

@article{MTMT:31041478,
	title = {Effects of calcium-binding sites in the S2-S3 loop on human and Nematostella vectensis TRPM2 channel gating processes},
	url = {https://m2.mtmt.hu/api/publication/31041478},
	author = {Luo, Yu-huan and Yu, Xia-fei and Ma, Cheng and Yang, Fan and Yang, Wei},
	doi = {10.1631/jzus.B1900477},
	journal-iso = {J ZHEJIANG UNIV-SC B},
	journal = {JOURNAL OF ZHEJIANG UNIVERSITY-SCIENCE B},
	volume = {20},
	unique-id = {31041478},
	issn = {1673-1581},
	abstract = {As a crucial signaling molecule, calcium plays a critical role in many physiological and pathological processes by regulating ion channel activity. Recently, one study resolved the structure of the transient receptor potential melastatin 2 (TRPM2) channel from Nematostella vectensis (nvTRPM2). This identified a calcium-binding site in the S2-S3 loop, while its effect on channel gating remains unclear. Here, we investigated the role of this calcium-binding site in both nvTRPM2 and human TRPM2 (hTRPM2) by mutagenesis and patch-clamp recording. Unlike hTRPM2, nvTRPM2 cannot be activated by calcium alone. Moreover, the inactivation rate of nvTRPM2 was decreased as intracellular calcium concentration was increased. In addition, our results showed that the four key residues in the calcium-binding site of S2-S3 loop have similar effects on the gating processes of nvTRPM2 and hTRPM2. Among them, the mutations at negatively charged residues (glutamate and aspartate) substantially decreased the currents of nvTRPM2 and hTRPM2. This suggests that these sites are essential for calcium-dependent channel gating. For the charge-neutralizing residues (glutamine and asparagine) in the calcium-binding site, our data showed that glutamine mutating to alanine or glutamate did not affect the channel activity, but glutamine mutating to lysine caused loss of function. Asparagine mutating to aspartate still remained functional, while asparagine mutating to alanine or lysine led to little channel activity. These results suggest that the side chain of glutamine has a less contribution to channel gating than does asparagine. However, our data indicated that both glutamine mutating to alanine or glutamate and asparagine mutating to aspartate accelerated the channel inactivation rate, suggesting that the calcium-binding site in the S2-S3 loop is important for calcium-dependent channel inactivation. Taken together, our results uncovered the effect of four key residues in the S2-S3 loop of TRPM2 on the TRPM2 gating process.},
	keywords = {IDENTIFICATION; CALCIUM-BINDING SITE; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; channel activation; TRPM2; channel inactivation; S2-S3 loop},
	year = {2019},
	eissn = {1862-1783},
	pages = {972-982}
}

@article{MTMT:30628105,
	title = {TRPM2 Channel in Microglia as a New Player in Neuroinflammation Associated With a Spectrum of Central Nervous System Pathologies.},
	url = {https://m2.mtmt.hu/api/publication/30628105},
	author = {Malko, Philippa and Syed Mortadza, Sharifah A and McWilliam, Joseph and Jiang, Lin-Hua},
	doi = {10.3389/fphar.2019.00239},
	journal-iso = {FRONT PHARMACOL},
	journal = {FRONTIERS IN PHARMACOLOGY},
	volume = {10},
	unique-id = {30628105},
	abstract = {Microglial cells in the central nervous system (CNS) are crucial in maintaining a healthy environment for neurons to function properly. However, aberrant microglial cell activation can lead to excessive generation of neurotoxic proinflammatory mediators and neuroinflammation, which represents a contributing factor in a wide spectrum of CNS pathologies, including ischemic stroke, traumatic brain damage, Alzheimer's disease, Parkinson's disease, multiple sclerosis, psychiatric disorders, autism spectrum disorders, and chronic neuropathic pain. Oxidative stress is a salient and common feature of these conditions and has been strongly implicated in microglial cell activation and neuroinflammation. The transient receptor potential melastatin-related 2 (TRPM2) channel, an oxidative stress-sensitive calcium-permeable cationic channel, is highly expressed in microglial cells. In this review, we examine the recent studies that provide evidence to support an important role for the TRPM2 channel, particularly TRPM2-mediated Ca2+ signaling, in mediating microglial cell activation, generation of proinflammatory mediators and neuroinflammation, which are of relevance to CNS pathologies. These findings lead to a growing interest in the TRPM2 channel, a new player in neuroinflammation, as a novel therapeutic target for CNS diseases.},
	keywords = {neuroinflammation; TRPM2 channel; CNS pathologies; microglial cell activation; proinflammatory mediators},
	year = {2019},
	eissn = {1663-9812}
}

@article{MTMT:30673027,
	title = {TRPM2 in Cancer.},
	url = {https://m2.mtmt.hu/api/publication/30673027},
	author = {Miller, Barbara A},
	doi = {10.1016/j.ceca.2019.03.002},
	journal-iso = {CELL CALCIUM},
	journal = {CELL CALCIUM},
	volume = {80},
	unique-id = {30673027},
	issn = {0143-4160},
	abstract = {The TRP ion channel TRPM2 has an essential function in cell survival and protects the viability of a number of cell types after oxidative stress. It is highly expressed in many cancers including breast, prostate, and pancreatic cancer, melanoma, leukemia, and neuroblastoma, suggesting it promotes cancer cell survival. TRPM2 is activated by production of ADP-ribose (ADPR) following oxidative stress, which binds to the C-terminus of TRPM2, resulting in channel opening. In a number of cancers including neuroblastoma, TRPM2 has been shown to preserve viability and mechanisms have been identified. Activation of TRPM2 results in expression of transcription factors and kinases important in cell proliferation and survival including HIF-1/2α, CREB, nuclear factor (erythroid-derived 2)-related factor-2 (Nrf2), and Pyk2, and Src phosphorylation. Together, HIF-1/2α and CREB regulate expression of genes encoding proteins with roles in mitochondrial function including members of the electron transport complex involved in ATP production. These contribute to lower mitochondrial ROS production while expression of antioxidants regulated by HIF-1/2α, FOXO3a, CREB, and Nrf2 is maintained. CREB is also important in control of expression of key proteins involved in autophagy. When TRPM2-mediated calcium influx is inhibited, mitochondria are dysfunctional, cellular bioenergetics are reduced, production of ROS is increased, and autophagy and DNA repair are impaired, decreasing tumor growth and increasing chemotherapy sensitivity. Inhibition of TRPM2 expression or function results in decreased tumor proliferation and/or viability in many malignancies including breast, gastric, pancreatic, prostate, head and neck cancers, melanoma, neuroblastoma, and T-cell and acute myelogenous leukemia. However, in a small number of malignancies, activation of TRPM2 rather than inhibition has been reported to reduce tumor cell survival. Here, TRPM2-mediated Ca2+ signaling and mechanisms of regulation of cancer cell growth and survival are reviewed and controversies discussed. Evidence suggests that targeting TRPM2 may be a novel therapeutic approach in many cancers.},
	keywords = {CANCER; Mitochondria; CREB; ROS; HIF-1α; TRPM2},
	year = {2019},
	eissn = {1532-1991},
	pages = {8-17}
}

@article{MTMT:30673086,
	title = {Frontiers in Cryo Electron Microscopy of Complex Macromolecular Assemblies.},
	url = {https://m2.mtmt.hu/api/publication/30673086},
	author = {Ognjenović, Jana and Grisshammer, Reinhard and Subramaniam, Sriram},
	doi = {10.1146/annurev-bioeng-060418-052453},
	journal-iso = {ANNU REV BIOMED ENG},
	journal = {ANNUAL REVIEW OF BIOMEDICAL ENGINEERING},
	volume = {21},
	unique-id = {30673086},
	issn = {1523-9829},
	abstract = {In recent years, cryo electron microscopy (cryo-EM) technology has been transformed with the development of better instrumentation, direct electron detectors, improved methods for specimen preparation, and improved software for data analysis. Analyses using single-particle cryo-EM methods have enabled determination of structures of proteins with sizes smaller than 100 kDa and resolutions of ∼2 Å in some cases. The use of electron tomography combined with subvolume averaging is beginning to allow the visualization of macromolecular complexes in their native environment in unprecedented detail. As a result of these advances, solutions to many intractable challenges in structural and cell biology, such as analysis of highly dynamic soluble and membrane-embedded protein complexes or partially ordered protein aggregates, are now within reach. Recent reports of structural studies of G protein-coupled receptors, spliceosomes, and fibrillar specimens illustrate the progress that has been made using cryo-EM methods, and are the main focus of this review. Expected final online publication date for the Annual Review of Biomedical Engineering Volume 21 is June 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.},
	year = {2019},
	eissn = {1545-4274},
	pages = {395-415}
}

@{MTMT:30766404,
	title = {Molecular Determinants of Cholesterol Binding to Soluble and Transmembrane Protein Domains},
	url = {https://m2.mtmt.hu/api/publication/30766404},
	author = {Ounjian, Jessica and Bukiya, Anna N. and Rosenhouse-Dantsker, Avia},
	booktitle = {Direct Mechanisms in Cholesterol Modulation of Protein Function},
	doi = {10.1007/978-3-030-14265-0_3},
	unique-id = {30766404},
	abstract = {Cholesterol-protein interactions play a critical role in lipid metabolism and maintenance of cell integrity. To elucidate the molecular mechanisms underlying these interactions, a growing number of studies have focused on determining the crystal structures of a variety of proteins complexed with cholesterol. These include structures in which cholesterol binds to transmembrane domains, and structures in which cholesterol interacts with soluble ones. However, it remains unknown whether there are differences in the prerequisites for cholesterol binding to these two types of domains. Thus, to define the molecular determinants that characterize the binding of cholesterol to these two distinct protein domains, we employed the database of crystal structures of proteins complexed with cholesterol. Our analysis suggests that cholesterol may bind more strongly to soluble domains than to transmembrane domains. The interactions between cholesterol and the protein in both cases critically depends on hydrophobic and aromatic residues. In addition, cholesterol binding sites in both types of domains involve polar and/or charged residues. However, the percentage of appearance of the different types of polar/charged residues in cholesterol binding sites differs between soluble and transmembrane domains. No differences were observed in the conformational characteristics of the cholesterol molecules bound to soluble versus transmembrane protein domains suggesting that cholesterol is insensitive to the environment provided by the different protein domains.},
	keywords = {LIPID-PROTEIN INTERACTIONS; TRANSMEMBRANE DOMAIN; Cholesterol binding; Soluble domain; Steroid binding site},
	year = {2019},
	pages = {47-66}
}

@article{MTMT:31042608,
	title = {The anthelmintic drug praziquantel activates a schistosome transient receptor potential channel},
	url = {https://m2.mtmt.hu/api/publication/31042608},
	author = {Park, S.-K. and Gunaratne, G.S. and Chulkov, E.G. and Moehring, F. and McCusker, P. and Dosa, P.I. and Chan, J.D. and Stucky, C.L. and Marchant, J.S.},
	doi = {10.1074/jbc.AC119.011093},
	journal-iso = {J BIOL CHEM},
	journal = {JOURNAL OF BIOLOGICAL CHEMISTRY},
	volume = {294},
	unique-id = {31042608},
	issn = {0021-9258},
	year = {2019},
	eissn = {1083-351X},
	pages = {18873-18880}
}

@{MTMT:30766400,
	title = {Cholesterol Binding Sites in Inwardly Rectifying Potassium Channels},
	url = {https://m2.mtmt.hu/api/publication/30766400},
	author = {Rosenhouse-Dantsker, Avia},
	booktitle = {Direct Mechanisms in Cholesterol Modulation of Protein Function},
	doi = {10.1007/978-3-030-14265-0_7},
	unique-id = {30766400},
	abstract = {Inwardly rectifying potassium (Kir) channels play a variety of critical cellular roles including modulating membrane excitability in neurons, cardiomyocytes and muscle cells, and setting the resting membrane potential, heart rate, vascular tone, insulin release, and salt flow across epithelia. These processes are regulated by a variegated list of modulators. In particular, in recent years, cholesterol has been shown to modulate a growing number of Kir channels. Subsequent to the discovery that members of the Kir2 subfamily were down-regulated by cholesterol, we have shown that members of several other Kir subfamilies were also modulated by cholesterol. However, not all cholesterol sensitive Kir channels were down-regulated by cholesterol. Our recent studies focused on three Kir channels: Kir2.1 (IRK1), Kir3.2(boolean AND) (GIRK2(boolean AND)) and Kir3.4* (GIRK4*). Among these, Kir2.1 was down-regulated by cholesterol whereas Kir3.2(boolean AND) and Kir3.4* were both up-regulated by cholesterol. Despite the opposite impact of cholesterol on these Kir3 channels compared to Kir2.1, putative cholesterol binding sites in all three channels were identified in equivalent transmembrane domains. Interestingly, however, there are intriguing differences in the specific residues that interact with the cholesterol molecule in these Kir channels. Here we compare and contrast the molecular characteristics of the putative cholesterol binding sites in the three channels, and discuss the potential implications of the differences for the impact of cholesterol on ion channels.},
	keywords = {ION CHANNELS; cholesterol; Protein-lipid interaction; GIRK channels; Kir channels; Channel modulation},
	year = {2019},
	pages = {119-138}
}

@article{MTMT:34504070,
	title = {Case Report: Investigation and molecular genetic diagnosis of familial hypomagnesaemia},
	url = {https://m2.mtmt.hu/api/publication/34504070},
	author = {Sayer, J.A. and Willows, J. and Al, Badi M. and Richardson, C. and Al, Sinani A. and Edwards, N. and Rice, S.},
	doi = {10.12688/f1000research.19006.2},
	journal-iso = {F1000RESEARCH},
	journal = {F1000RESEARCH},
	volume = {8},
	unique-id = {34504070},
	issn = {2046-1402},
	abstract = {Genetic mutations causing familial hypomagnesaemia syndromes are well-recognised. Affected patients can present with severe symptoms of hypomagnesaemia, such as seizures or cardiac arrhythmia. We report an affected child, from a consanguineous family, who presented in the first weeks of life with seizures secondary to hypomagnesaemia, without other associated clinical features. We performed whole exome sequencing in the affected child and segregation analysis within the family, which revealed a novel homozygous missense mutation in TRPM6, which was confirmed as a heterozygous allele in both parents and two younger siblings who had transient hypomagnesaemia. Using in silico modelling, we provide evidence that the missense variant p.(K1098E) in TRPM6 is pathogenic, as it disrupts stabilising TRP domain interactions. Management of familial hypomagnesaemia relies on prompt recognition, early magnesium replacement and lifelong monitoring. © 2019 Willows J et al.},
	keywords = {Female; ARTICLE; human; Child; Genetic variability; molecular genetics; case report; clinical article; preschool child; Informed Consent; HOMOZYGOSITY; missense mutation; familial disease; tonic clonic seizure; magnesium ion; magnesium sulfate; Parathyroid Hormone; hypocalcemia; molecular diagnosis; magnesium blood level; gluconate calcium; Whole exome sequencing; Sanger sequencing; transient receptor potential channel M6; hypomagnesemia; TRPM6; Oman; Hypomagnesaemia; With secondary hypocalcaemia; urinary excretion fraction; familial hypomagnesemia; TRPM6 gene},
	year = {2019}
}

@article{MTMT:31042614,
	title = {Progress on structural biology of voltage-gated ion channels},
	url = {https://m2.mtmt.hu/api/publication/31042614},
	author = {Song, Fangjun and Guo, Jiangtao},
	journal-iso = {JOURNAL OF ZHEJIANG UNIVERSITY MEDICAL SCIENCES},
	journal = {JOURNAL OF ZHEJIANG UNIVERSITY MEDICAL SCIENCES},
	volume = {48},
	unique-id = {31042614},
	issn = {1008-9292},
	abstract = {Ion channels mediate ion transport across membranes,and play vital roles in processes of matter exchange,energy transfer and signal transduction in living organisms.Recently,structural studies of ion channels have greatly advanced our understanding of their ion selectivity and gating mechanisms.Structural studies of voltage-gated potassium channels elucidate the structural basis for potassium selectivity and voltage-gating mechanism;structural studies of voltage-gated sodium channels reveal their slow and fast inactivation mechanisms;and structural studies of transient receptor potential (TRP) channels provide complex and diverse structures of TRP channels,and their ligand gating mechanisms.In the article we summarize recent progress on ion channel structural biology,and outlook the prospect of ion channel structural biology in the future.},
	keywords = {ION CHANNELS; protein structure; voltage-gating; Ionselectivity; Ligandgating},
	year = {2019},
	pages = {25-33}
}

@article{MTMT:30766412,
	title = {Human mutations highlight an intersubunit cation-pi bond that stabilizes the closed but not open or inactivated states of TRPV channels},
	url = {https://m2.mtmt.hu/api/publication/30766412},
	author = {Teng, Jinfeng and Anishkin, Andriy and Kung, Ching and Blount, Paul},
	doi = {10.1073/pnas.1820673116},
	journal-iso = {P NATL ACAD SCI USA},
	journal = {PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA},
	volume = {116},
	unique-id = {30766412},
	issn = {0027-8424},
	abstract = {An adequate response of a living cell to the ever-changing environment requires integration of numerous sensory inputs. In many cases, it can be achieved even at the level of a single receptor molecule. Polymodal transient receptor potential (TRP) channels have been shown to integrate mechanical, chemical, electric, and thermal stimuli. Inappropriate gating can lead to pathologies. Among the >60 known TRP vanilloid subfamily (V) 4 mutations that interfere with bone development are Y602C or R616Q at the S4-S5 linker. A cation-t bond between the conservative residues Y602 and R616 of neighboring subunits appears likely in many homologous channel structures in a closed state. Our experiments with TRPV4 mutants indicate that the resting closed state remains stable while the bond is substituted by a salt bridge or disulfide bond, whereas disruption of the contact by mutations like Y602C or R616Q produces gain-of-function phenotypes when TRPV4 is heterologously expressed in the Xenopus oocyte or yeast. Our data indicate that the Y602-R616 cation-t interactions link the four S4-S5 linker helices together, forming a girdle backing the closed gate. Analogous cation-a bonds and the girdle are seen in many closed TRP channel structures. This girdle is not observed in the cryo-EM structure of amphibian TRPV4 (Protein Data Bank ID code 61313.1), which appears to be in a different impermeable state we hypothesize this is the inactivated state.},
	keywords = {LIPIDS; TRP CHANNELS; gating; TRP domain; opening mechanism},
	year = {2019},
	eissn = {1091-6490},
	pages = {9410-9416}
}

@article{MTMT:31042604,
	title = {Transient receptor potential channels and endothelial cell calcium signaling},
	url = {https://m2.mtmt.hu/api/publication/31042604},
	author = {Thakore, P. and Earley, S.},
	doi = {10.1002/cphy.c180034},
	journal-iso = {COMPR PHYSIOL},
	journal = {COMPREHENSIVE PHYSIOLOGY},
	volume = {9},
	unique-id = {31042604},
	issn = {2040-4603},
	year = {2019},
	eissn = {2040-4603},
	pages = {1249-1277}
}

@article{MTMT:30766411,
	title = {Transient Receptor Potential Channels and Calcium Signaling},
	url = {https://m2.mtmt.hu/api/publication/30766411},
	author = {Vangeel, Laura and Voets, Thomas},
	doi = {10.1101/cshperspect.a035048},
	journal-iso = {CSH PERSPECT BIOL},
	journal = {COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY},
	volume = {11},
	unique-id = {30766411},
	issn = {1943-0264},
	abstract = {Transient receptor potential (TRP) cation channels play diverse roles in cellular Ca2+ signaling. First, as Ca2+-permeable channels that respond to a variety of stimuli, TRP channels can directly initiate cellular Ca2+ signals. Second, as nonselective cation channels, TRP channel activation leads to membrane depolarization, influencing Ca2+ influx via voltage-gated and store-operated Ca2+ channels. Finally, Ca2+ modulates the activity of most TRP channels, allowing them to function as molecular effectors downstream of intracellular Ca2+ signals. Whereas the TRP channel field has long been devoid of detailed channel structures, recent advances, particularly in cryo-electron microscopy-based structural approaches, have yielded a flurry of TRP channel structures, including members from all seven subfamilies. These structures, in conjunction with mutagenesis-based functional approaches, provided important new insights into the mechanisms whereby TRP channels permeate and sense Ca2+. These insights will be highly instrumental in the rational design of novel treatments for the multitude of TRP channel-related diseases.},
	year = {2019},
	eissn = {1943-0264}
}

@{MTMT:30766402,
	title = {Modes of Cholesterol Binding in Membrane Proteins: A Joint Analysis of 73 Crystal Structures},
	url = {https://m2.mtmt.hu/api/publication/30766402},
	author = {Wang, Cong and Ralko, Arthur and Ren, Zhong and Rosenhouse-Dantsker, Avia and Yang, Xiaojing},
	booktitle = {Direct Mechanisms in Cholesterol Modulation of Protein Function},
	doi = {10.1007/978-3-030-14265-0_4},
	unique-id = {30766402},
	abstract = {Cholesterol is a highly asymmetric lipid molecule. As an essential constituent of the cell membrane, cholesterol plays important structural and signaling roles in various biological processes. The first high-resolution crystal structure of a transmembrane protein in complex with cholesterol was a human beta(2)-adrenergic receptor structure deposited to the Protein Data Bank in 2007. Since then, the number of the cholesterol-bound crystal structures has grown considerably providing an invaluable resource for obtaining insights into the structural characteristics of cholesterol binding. In this work, we examine the spatial and orientation distributions of cholesterol relative to the protein framework in a collection of 73 crystal structures of membrane proteins. To characterize the cholesterol-protein interactions, we apply singular value decomposition to an array of interatomic distances, which allows us to systematically assess the flexibility and variability of cholesterols in transmembrane proteins. Together, this joint analysis reveals the common characteristics among the observed cholesterol structures, thereby offering important guidelines for prediction and modification of potential cholesterol binding sites in transmembrane proteins.},
	keywords = {membrane protein; crystal structure; Singular value decomposition; distance matrix; Cholesterol-protein interactions},
	year = {2019},
	pages = {67-86}
}

@article{MTMT:30870434,
	title = {Case report: Investigation and molecular genetic diagnosis of familial hypomagnesaemia: A case report [version 1; peer review: 1 approved, 3 approved with reservations]},
	url = {https://m2.mtmt.hu/api/publication/30870434},
	author = {Willows, J. and Al, Badi M. and Richardson, C. and Edwards, N. and Rice, S. and Sayer, J.A.},
	doi = {10.12688/f1000research.19006.1},
	journal-iso = {F1000RESEARCH},
	journal = {F1000RESEARCH},
	volume = {8},
	unique-id = {30870434},
	issn = {2046-1402},
	keywords = {molecular genetics; case report; TRPM6; Hypomagnesaemia; With secondary hypocalcaemia},
	year = {2019}
}

@article{MTMT:30766410,
	title = {The oncogenic roles of TRPM ion channels in cancer},
	url = {https://m2.mtmt.hu/api/publication/30766410},
	author = {Wong, Kah Keng and Banham, Alison H. and Yaacob, Nik Soriani and Husna, Siti Muhamad Nur},
	doi = {10.1002/jcp.28168},
	journal-iso = {J CELL PHYSIOL},
	journal = {JOURNAL OF CELLULAR PHYSIOLOGY},
	volume = {234},
	unique-id = {30766410},
	issn = {0021-9541},
	abstract = {Transient receptor potential (TRP) proteins are a diverse family of ion channels present in multiple types of tissues. They function as gatekeepers for responses to sensory stimuli including temperature, vision, taste, and pain through their activities in conducting ion fluxes. The TRPM (melastatin) subfamily consists of eight members (i.e., TRPM1-8), which collectively regulate fluxes of various types of cations such as K+, Na+, Ca2+, and Mg2+. Growing evidence in the past two decades indicates that TRPM ion channels, their isoforms, or long noncoding RNAs encoded within the locus may be oncogenes involved in the regulation of cancer cell growth, proliferation, autophagy, invasion, and epithelial-mesenchymal transition, and their significant association with poor clinical outcomes of cancer patients. In this review, we describe and discuss recent findings implicating TRPM channels in different malignancies, their functions, mechanisms, and signaling pathways involved in cancers, as well as summarizing their normal physiological functions and the availability of ion channel pharmacological inhibitors.},
	keywords = {ISOFORMS; Oncogenes; LncRNA; TRPM},
	year = {2019},
	eissn = {1097-4652},
	pages = {14556-14573},
	orcid-numbers = {Wong, Kah Keng/0000-0001-7359-6202}
}

@article{MTMT:30793128,
	title = {Mechanism of TRPM2 channel gating revealed by cryo-EM},
	url = {https://m2.mtmt.hu/api/publication/30793128},
	author = {Xia, S. and Wang, L. and Fu, T.-M. and Wu, H.},
	doi = {10.1111/febs.14939},
	journal-iso = {FEBS J},
	journal = {FEBS JOURNAL},
	volume = {286},
	unique-id = {30793128},
	issn = {1742-464X},
	keywords = {calcium; ion channel; structure; gating; cryo-EM; TRP channel; TRPM2; ADPR},
	year = {2019},
	eissn = {1742-4658},
	pages = {3333-3339}
}

@article{MTMT:31042613,
	title = {Structural modeling of selectivity filter in transient receptor pontential melastatin 8 ion channel},
	url = {https://m2.mtmt.hu/api/publication/31042613},
	author = {Xu, Lizhen and Yang, Fan},
	journal-iso = {JOURNAL OF ZHEJIANG UNIVERSITY MEDICAL SCIENCES},
	journal = {JOURNAL OF ZHEJIANG UNIVERSITY MEDICAL SCIENCES},
	volume = {48},
	unique-id = {31042613},
	issn = {1008-9292},
	abstract = {Objective:To construct a three-dimensional structural model for the selectivity filter in the transient receptor pontential melastatin 8 (TRPM8) ion channel.Methods:In the Rosetta computational structural biology suite,multiple rounds of de novo modeling with the kinematic loop closure algorithm were performed.Results:After nine rounds of computational modeling,we obtained the models of the selectivity filter within the TRPM8 channel with the lowest energy and high convergence.The model showed that the sidechain of D918 points were away from the central ion permeation pathway,while the sidechains of Q914,D920 and T923 pointed towards it.The glycosylation site N934 was located outside the pore region and its side chain directed to the extracellular water environment.Conclusion:A three-dimensional structural model for the selectivity filter in the TRPM8 ion channel was constructed,which provides reliable structural information for exploring the mechanism of ion selectivity.},
	keywords = {amino acid sequence; Transient Receptor Potential Channels; TRPM Cation Channels},
	year = {2019},
	pages = {19-24}
}

@article{MTMT:31042612,
	title = {Extraction and purification of NUDT9 homology domain of human transient receptor potential melastatin 2 channel},
	url = {https://m2.mtmt.hu/api/publication/31042612},
	author = {Ye, Peiwu and Yu, Xiafei and Ma, Cheng and Yang, Wei},
	journal-iso = {JOURNAL OF ZHEJIANG UNIVERSITY MEDICAL SCIENCES},
	journal = {JOURNAL OF ZHEJIANG UNIVERSITY MEDICAL SCIENCES},
	volume = {48},
	unique-id = {31042612},
	issn = {1008-9292},
	abstract = {Objective:To develop methods of extraction and purification of Cterminal NUDT9 homology domain of human transient receptor potential melastatin 2(TRPM2) channel.Methods:After sonication and centrifuge of Escherichia coli strain Rosetta (DE3) which was induced by isopropylthio-beta-D-galactoside,GST-NUDT9-H was collected after the binding of supernatant with GST beads and eluted with reduced glutathione.Then the elution buffer containing fusion protein was purified by size exclusion chromatography after concentration and centrifuge.Finally,with the cleavage of thrombin and binding with the GST beads,NUDT9-H with high purity in supernatant was collected.Results:The GST-NUDT9-H fusion protein was stabilized with lysis buffer containing 0.5% n-dodecyl- beta- d-maltoside (DDM),and wash buffer containing 0.025% DDM in size-exclusion chromatography system,and finally the NUDT9-H with high purity was obtained after cleaved by thrombin (1 U/2 mg fusion protein) for 24 h.Conclusion:Due to the poor stability of NUDT9-H,it is necessary to add DDM in extraction and purification buffer to stabilize the conformation of NUDT9-H,so as to increase its yields and purity.},
	keywords = {Transient Receptor Potential Channels; Pyrophosphatases/pharmacology; Recombinant fusion proteins/isolation & purification},
	year = {2019},
	pages = {5-11}
}

@article{MTMT:30789149,
	title = {Visualizing structural transitions of ligand-dependent gating of the TRPM2 channel},
	url = {https://m2.mtmt.hu/api/publication/30789149},
	author = {Yin, Ying and Wu, Mengyu and Hsw, Allen L. and Borschel, William F. and Borgnia, Mario J. and Lander, Gabriel C. and Lee, Seok-Yong},
	doi = {10.1038/s41467-019-11733-5},
	journal-iso = {NAT COMMUN},
	journal = {NATURE COMMUNICATIONS},
	volume = {10},
	unique-id = {30789149},
	issn = {2041-1723},
	abstract = {The transient receptor potential melastatin 2 (TRPM2) channel plays a key role in redox sensation in many cell types. Channel activation requires binding of both ADP-ribose (ADPR) and Ca2+. The recently published TRPM2 structures from Danio rerio in the ligand-free and the ADPR/Ca2+-bound conditions represent the channel in closed and open states, which uncovered substantial tertiary and quaternary conformational rearrangements. However, it is unclear how these rearrangements are achieved within the tetrameric channel during channel gating. Here we report the cryo-electron microscopy structures of Danio rerio TRPM2 in the absence of ligands, in complex with Ca2+ alone, and with both ADPR and Ca2+, resolved to similar to 4.3 angstrom, similar to 3.8 angstrom, and similar to 4.2 angstrom, respectively. In contrast to the published results, our studies capture ligand-bound TRPM2 structures in two-fold symmetric intermediate states, offering a glimpse of the structural transitions that bridge the closed and open conformations.},
	year = {2019},
	eissn = {2041-1723}
}

@article{MTMT:30766408,
	title = {Direct Gating of the TRPM2 Channel by cADPR via Specific Interactions with the ADPR Binding Pocket},
	url = {https://m2.mtmt.hu/api/publication/30766408},
	author = {Yu, Peilin and Liu, Zhenming and Yu, Xiafei and Ye, Peiwu and Liu, Huan and Xue, Xiwen and Yang, Lixin and Li, Zhongtang and Wu, Yang and Fang, Cheng and Zhao, Yong Juan and Yang, Fan and Luo, Jian Hong and Jiang, Lin-Hua and Zhang, Liangren and Zhang, Lihe and Yang, Wei},
	doi = {10.1016/j.celrep.2019.05.067},
	journal-iso = {CELL REP},
	journal = {CELL REPORTS},
	volume = {27},
	unique-id = {30766408},
	issn = {2211-1247},
	abstract = {cADPR is a well-recognized signaling molecule by modulating the RyRs, but considerable debate exists regarding whether cADPR can bind to and gate the TRPM2 channel, which mediates oxidative stress signaling in diverse physiological and pathological processes. Here, we show that purified cADPR evoked TRPM2 channel currents in both whole-cell and cell-free single-channel recordings and specific binding of cADPR to the purified NUDT9-H domain of TRPM2 by surface plasmon resonance. Furthermore, by combining computational modeling with electrophysiological recordings, we show that the TRPM2 channels carrying point mutations at H1346, T1347, L1379, S1391, E1409, and L1484 possess distinct sensitivity profiles for ADPR and cADPR. These results clearly indicate cADPR is a bona fide activator at the TRPM2 channel and clearly delineate the structural basis for cADPR binding, which not only lead to a better understanding in the gating mechanism of TRPM2 channel but also shed light on a cADPR-induced RyRs-independent Ca2+ signaling mechanism.},
	year = {2019},
	eissn = {2211-1247},
	pages = {3684-+}
}

@article{MTMT:30642642,
	title = {Purification of Functional Human TRP Channels Recombinantly Produced in Yeast},
	url = {https://m2.mtmt.hu/api/publication/30642642},
	author = {Zhang, Liying and Wang, Kaituo and Klaerke, Dan Arne and Calloe, Kirstine and Lowrey, Lillian and Pedersen, Per Amstrup and Gourdon, Pontus and Gotfryd, Kamil},
	doi = {10.3390/cells8020148},
	journal-iso = {CELLS-BASEL},
	journal = {CELLS},
	volume = {8},
	unique-id = {30642642},
	abstract = {(1) Background: Human transient receptor potential (TRP) channels constitute a large family of ion-conducting membrane proteins that allow the sensation of environmental cues. As the dysfunction of TRP channels contributes to the pathogenesis of many widespread diseases, including cardiac disorders, these proteins also represent important pharmacological targets. TRP channels are typically produced using expensive and laborious mammalian or insect cell-based systems. (2) Methods: We demonstrate an alternative platform exploiting the yeast Saccharomyces cerevisiae capable of delivering high yields of functional human TRP channels. We produce 11 full-length human TRP members originating from four different subfamilies, purify a selected subset of these to a high homogeneity and confirm retained functionality using TRPM8 as a model target. (3) Results: Our findings demonstrate the potential of the described production system for future functional, structural and pharmacological studies of human TRP channels.},
	keywords = {ION CHANNELS; YEAST; Saccharomyces cerevisiae; sensors; protein purification; overproduction; production platform; transient receptor potential (TRP) channels},
	year = {2019},
	eissn = {2073-4409}
}