@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:34176591, title = {Role of TRP Channels in Liver-Related Diseases}, url = {https://m2.mtmt.hu/api/publication/34176591}, author = {Liu, Yusheng and Lyu, Yihan and Zhu, Lijuan and Wang, Hongmei}, doi = {10.3390/ijms241512509}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {34176591}, issn = {1661-6596}, abstract = {The liver plays a crucial role in preserving the homeostasis of an entire organism by metabolizing both endogenous and exogenous substances, a process that relies on the harmonious interactions of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells (KCs), and vascular endothelial cells (ECs). The disruption of the liver's normal structure and function by diverse pathogenic factors imposes a significant healthcare burden. At present, most of the treatments for liver disease are palliative in nature, rather than curative or restorative. Transient receptor potential (TRP) channels, which are extensively expressed in the liver, play a crucial role in regulating intracellular cation concentration and serve as the origin or intermediary stage of certain signaling pathways that contribute to liver diseases. This review provides an overview of recent developments in liver disease research, as well as an examination of the expression and function of TRP channels in various liver cell types. Furthermore, we elucidate the molecular mechanism by which TRP channels mediate liver injury, liver fibrosis, and hepatocellular carcinoma (HCC). Ultimately, the present discourse delves into the current state of research and extant issues pertaining to the targeting of TRP channels in the treatment of liver diseases and other ailments. Despite the numerous obstacles encountered, TRP channels persist as an extremely important target for forthcoming clinical interventions aimed at treating liver diseases.}, keywords = {IN-VITRO; DIFFERENTIAL EXPRESSION; ION-CHANNEL; DOUBLE-BLIND; liver injury; Liver Diseases; liver fibrosis; TRP CHANNELS; HEPATIC STELLATE CELLS; CALCIUM-ENTRY; Biochemistry & Molecular Biology; Kupffer Cells; PHARMACOLOGICAL INHIBITION; HEPATOCELLULAR-CARCINOMA CELLS}, year = {2023}, eissn = {1422-0067} } @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: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:33318846, title = {TRPM2 causes sensitization to oxidative stress but attenuates high-temperature injury in the sea anemone Nematostella vectensis}, url = {https://m2.mtmt.hu/api/publication/33318846}, author = {Ehrlich, Wiebke and Gahan, James M. and Rentzsch, Fabian and Kuehn, Frank J. P.}, doi = {10.1242/jeb.243717}, journal-iso = {J EXP BIOL}, journal = {JOURNAL OF EXPERIMENTAL BIOLOGY}, volume = {225}, unique-id = {33318846}, issn = {0022-0949}, abstract = {In humans, the cation channel TRPM2 (HsTRPM2) has been intensively studied because it is involved in oxidative stress-mediated apoptosis and also contributes to temperature regulation. The gating mechanism of TRPM2 is quite complex, with a C-terminally localized enzyme domain playing a crucial role. The analysis of orthologues of TRPM2, in particular from the distantly related marine invertebrate Nematostella vectensis (NvTRPM2), revealed that during evolution, the functional role of the endogenous enzyme domain of TRPM2 has undergone fundamental changes. In this study, we investigated whether these evolutionary differences also apply to the physiological functions of TRPM2. For this purpose, we generated a TRPM2 loss-offunction mutation in N. vectensis and compared the phenotypes of wild-type and mutant animals after exposure to either oxidative stress or high temperature. Our results show that under standard culture conditions, mutant animals are indistinguishable from wild-type animals in terms of morphology and development. However, exposure of the two experimental groups to different stressors revealed that TRPM2 causes sensitization to oxidative stress but attenuates high-temperature injury in N. vectensis. Therefore, NvTRPM2 plays opposite roles in the cellular response to these two different stressors. These findings reveal a similar physiological spectrum of activity of TRPM2 in humans and N. vectensis and open up the possibility of establishing N. vectensis as a model organism for the physiological function of TRPM2.}, keywords = {environmental stress; Nematostella vectensis; TRPM channels; NUDT9}, year = {2022}, eissn = {1477-9145}, pages = {43717-43717} } @article{MTMT:33063833, title = {The crystal structure of TRPM2 MHR1/2 domain reveals a conserved Zn2+-binding domain essential for structural integrity and channel activity}, url = {https://m2.mtmt.hu/api/publication/33063833}, author = {Sander, S. and Pick, J. and Gattkowski, E. and Fliegert, R. and Tidow, H.}, doi = {10.1002/pro.4320}, journal-iso = {PROTEIN SCI}, journal = {PROTEIN SCIENCE}, volume = {31}, unique-id = {33063833}, issn = {0961-8368}, abstract = {Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable, nonselective cation channel involved in diverse physiological processes such as immune response, apoptosis, and body temperature sensing. TRPM2 is activated by ADP-ribose (ADPR) and 2′-deoxy-ADPR in a Ca2+-dependent manner. While two distinct binding sites exist for ADPR that exert different functions dependent on the species, the involvement of either binding site regarding the superagonistic effect of 2′-deoxy-ADPR is not clear yet. Here, we report the crystal structure of the MHR1/2 domain of TRPM2 from zebrafish (Danio rerio), and show that both ligands bind to this domain and activate the channel. We identified a so far unrecognized Zn2+-binding domain that was not resolved in previous cryo-EM structures and that is conserved in most TRPM channels. In combination with patch clamp experiments we comprehensively characterize the effect of the Zn2+-binding domain on TRPM2 activation. Our results provide insight into a conserved motif essential for structural integrity and channel activity. © 2022 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.}, keywords = {Animals; metabolism; calcium; calcium; GENETICS; ZEBRAFISH; animal; Chemistry; Electrophysiology; ZINC; ZINC; ZINC; crystal structure; adenosine diphosphate ribose; adenosine diphosphate ribose; zebra fish; transient receptor potential channel M; TRPM Cation Channels; TRPM2; ADPR; 2′-deoxy-ADPR}, year = {2022}, eissn = {1469-896X} } @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:32188279, title = {Analysis of ligand binding and resulting conformational changes in pyrophosphatase NUDT9}, url = {https://m2.mtmt.hu/api/publication/32188279}, author = {Gattkowski, E. and Rutherford, T.J. and Möckl, F. and Bauche, A. and Sander, S. and Fliegert, R. and Tidow, H.}, doi = {10.1111/febs.16097}, journal-iso = {FEBS J}, journal = {FEBS JOURNAL}, unique-id = {32188279}, issn = {1742-464X}, abstract = {Nudix hydrolase 9 (NUDT9) is a member of the nucleoside linked to another moiety X (NUDIX) protein superfamily, which hydrolyses a broad spectrum of organic pyrophosphates from metabolic processes. ADP-ribose (ADPR) has been the only known endogenous substrate accepted by NUDT9 so far. The Ca2+-permeable transient receptor potential melastatin subfamily 2 (TRPM2) channel contains a homologous NUDT9-homology (NUDT9H) domain and is activated by ADPR. Sustained Ca2+ influx via ADPR-activated TRPM2 triggers apoptotic mechanisms. Thus, a precise regulation of cellular ADPR levels by NUDT9 is essential. A detailed characterization of the enzyme-substrate interaction would help to understand the high substrate specificity of NUDT9. Here, we analysed ligand binding to NUDT9 using a variety of biophysical techniques. We identified 2′-deoxy-ADPR as an additional substrate for NUDT9. Similar enzyme kinetics and binding affinities were determined for the two ligands. The high-affinity binding was preserved in NUDT9 containing the mutated NUDIX box derived from the human NUDT9H domain. NMR spectroscopy indicated that ADPR and 2′-deoxy-ADPR bind to the same binding site of NUDT9. Backbone resonance assignment and subsequent molecular docking allowed further characterization of the binding pocket. Substantial conformational changes of NUDT9 upon ligand binding were observed which might allow for the development of NUDT9-based ADPR fluorescence resonance energy transfer sensors that may help with the analysis of ADPR signalling processes in cells in the future. © 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies}, keywords = {LIGAND; CONFORMATIONAL CHANGE; TRPM2; ADPR; Pyrophosphatase; FRET sensor}, year = {2021}, eissn = {1742-4658} } @article{MTMT:32053849, title = {TRPM2 ion channels steer neutrophils towards a source of hydrogen peroxide}, url = {https://m2.mtmt.hu/api/publication/32053849}, author = {Morad, H. and Luqman, S. and Tan, C.-H. and Swann, V. and McNaughton, P.A.}, doi = {10.1038/s41598-021-88224-5}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {11}, unique-id = {32053849}, issn = {2045-2322}, abstract = {Neutrophils must navigate accurately towards pathogens in order to destroy invaders and thus defend our bodies against infection. Here we show that hydrogen peroxide, a potent neutrophil chemoattractant, guides chemotaxis by activating calcium-permeable TRPM2 ion channels and generating an intracellular leading-edge calcium “pulse”. The thermal sensitivity of TRPM2 activation means that chemotaxis towards hydrogen peroxide is strongly promoted by small temperature elevations, suggesting that an important function of fever may be to enhance neutrophil chemotaxis by facilitating calcium influx through TRPM2. Chemotaxis towards conventional chemoattractants such as LPS, CXCL2 and C5a does not depend on TRPM2 but is driven in a similar way by leading-edge calcium pulses. Other proposed initiators of neutrophil movement, such as PI3K, Rac and lyn, influence chemotaxis by modulating the amplitude of calcium pulses. We propose that intracellular leading-edge calcium pulses are universal drivers of the motile machinery involved in neutrophil chemotaxis. © 2021, The Author(s).}, year = {2021}, eissn = {2045-2322} } @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:31258315, title = {Synthesis of phosphonoacetate analogues of the second messenger adenosine 5′-diphosphate ribose (ADPR)}, url = {https://m2.mtmt.hu/api/publication/31258315}, author = {Baszczyňski, O. and Watt, J.M. and Rozewitz, M.D. and Fliegert, R. and Guse, A.H. and Potter, B.V.L.}, doi = {10.1039/c9ra09284f}, journal-iso = {RSC ADV}, journal = {RSC ADVANCES}, volume = {10}, unique-id = {31258315}, issn = {2046-2069}, abstract = {Adenosine 5′-diphosphate ribose (ADPR) is an intracellular signalling molecule generated from nicotinamide adenine dinucleotide (NAD+). Synthetic ADPR analogues can shed light on the mechanism of activation of ADPR targets and their downstream effects. Such chemical biology studies, however, are often challenging due to the negatively charged pyrophosphate that is also sensitive to cellular pyrophosphatases. Prior work on an initial ADPR target, the transient receptor potential cation channel TRPM2, showed complete pyrophosphate group replacement to be a step too far in maintaining biological activity. Thus, we designed ADPR analogues with just one of the negatively charged phosphate groups removed, by employing a phosphonoacetate linker. Synthesis of two novel phosphonoacetate ADPR analogues is described via tandem N,N′-dicyclohexylcarbodiimide coupling to phosphonoacetic acid. Neither analogue, however, showed significant agonist or antagonist activity towards TRPM2, underlining the importance of a complete pyrophosphate motif in activation of this particular receptor. © 2019 The Royal Society of Chemistry.}, keywords = {Chemical activation; DICYCLOHEXYLCARBODIIMIDE; second messenger; BIOACTIVITY; Pyrophosphatases; Negatively charged; Intracellular signalling; Downstream effects; Transient receptor potentials; Nicotinamide adenine dinucleotides}, year = {2020}, eissn = {2046-2069}, pages = {1776-1785} } @article{MTMT:31368948, title = {Characterization and optimization of the novel transient receptor potential melastatin 2 antagonist TaTM2Nx}, url = {https://m2.mtmt.hu/api/publication/31368948}, author = {Cruz-Torres, I. and Backos, D.S. and Herson, P.S.}, doi = {10.1124/mol.119.117549}, journal-iso = {MOL PHARMACOL}, journal = {MOLECULAR PHARMACOLOGY}, volume = {97}, unique-id = {31368948}, issn = {0026-895X}, abstract = {Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable channel activated by adenosine diphosphate ribose metabolites and oxidative stress. TRPM2 contributes to neuronal injury in the brain caused by stroke and cardiac arrest among other diseases including pain, inflammation, and cancer. However, the lack of specific inhibitors hinders the study of TRPM2 in brain pathophysiology. Here, we present the design of a novel TRPM2 antagonist, tatM2NX, which prevents ligand binding and TRPM2 activation. We used mutagenesis of tatM2NX to determine the structure-activity relationship and antagonistic mechanism on TRPM2 using whole-cell patch clamp and Calcium imaging in human embryonic kidney 293 cells with stable human TRPM2 expression. We show that tatM2NX inhibits over 90% of TRPM2 channel currents at concentrations as low as 2 mM. Moreover, tatM2NX is a potent antagonist with an IC50 of 396 nM. Our results from tatM2NX mutagenesis indicate that specific residues within the tatM2NX C terminus are required to confer antagonism on TRPM2. Therefore, the peptide tatM2NX represents a new tool for the study of TRPM2 function in cell biology and enhances our understanding of TRPM2 in disease. SIGNIFICANCE STATEMENT TatM2NX is a potent TRPM2 channel antagonist with the potential for clinical benefit in neurological diseases. This study characterizes interactions of tatM2NX with TRPM2 and the mechanism of action using structure-activity analysis. © 2020 by The American Society for Pharmacology and Experimental Therapeutics}, keywords = {Humans; PEPTIDES; metabolism; PEPTIDE; calcium; calcium; GENETICS; IMMUNOCYTOCHEMISTRY; ARTICLE; MOUSE; MUTAGENESIS; MUTAGENESIS; Nervous System Diseases; neurologic disease; human; Chemistry; priority journal; Dose-Response Relationship, Drug; nonhuman; dose response; animal model; animal experiment; brain ischemia; structure-activity relationship; Drug Antagonism; DRUG DESIGN; DRUG DESIGN; human cell; unclassified drug; protein expression; molecular model; neuroprotection; carboxy terminal sequence; transactivator protein; Patch-Clamp Techniques; molecular dynamics; Inhibitory Concentration 50; structure activity relation; ligand binding; Optical imaging; human cell culture; protein structure; calcium channel blocking agent; tat Gene Products, Human Immunodeficiency Virus; fluorescence imaging; HEK293 Cells; Molecular Dynamics Simulation; Intravital microscopy; Intravital microscopy; HEK293 cell line; IC50; whole cell patch clamp; patch clamp technique; transient receptor potential channel M3; transient receptor potential channel M; live cell imaging; TRPM Cation Channels; Oxidative stress; Oxidative stress; tatm2nx; TRPM2 protein, human}, year = {2020}, eissn = {1521-0111}, pages = {102-111} } @{MTMT:31042546, title = {Pyridine Nucleotide Metabolites and Calcium Release from Intracellular Stores}, url = {https://m2.mtmt.hu/api/publication/31042546}, author = {Galione, A. and Chuang, K.-T.}, booktitle = {Calcium Signaling (2nd edition)}, doi = {10.1007/978-3-030-12457-1_15}, volume = {1131}, unique-id = {31042546}, year = {2020}, pages = {371-394} } @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: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:31731758, title = {TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions}, url = {https://m2.mtmt.hu/api/publication/31731758}, author = {Malko, P. and Jiang, L.-H.}, doi = {10.1016/j.redox.2020.101755}, journal-iso = {REDOX BIOL}, journal = {REDOX BIOLOGY}, volume = {37}, unique-id = {31731758}, issn = {2213-2317}, abstract = {Oxidative stress resulting from the accumulation of high levels of reactive oxygen species is a salient feature of, and a well-recognised pathological factor for, diverse pathologies. One common mechanism for oxidative stress damage is via the disruption of intracellular ion homeostasis to induce cell death. TRPM2 is a non-selective Ca2+-permeable cation channel with a wide distribution throughout the body and is highly sensitive to activation by oxidative stress. Recent studies have collected abundant evidence to show its important role in mediating cell death induced by miscellaneous oxidative stress-inducing pathological factors, both endogenous and exogenous, including ischemia/reperfusion and the neurotoxicants amyloid-β peptides and MPTP/MPP+ that cause neuronal demise in the brain, myocardial ischemia/reperfusion, proinflammatory mediators that disrupt endothelial function, diabetogenic agent streptozotocin and diabetes risk factor free fatty acids that induce loss of pancreatic β-cells, bile acids that damage pancreatic acinar cells, renal ischemia/reperfusion and albuminuria that are detrimental to kidney cells, acetaminophen that triggers hepatocyte death, and nanoparticles that injure pericytes. Studies have also shed light on the signalling mechanisms by which these pathological factors activate the TRPM2 channel to alter intracellular ion homeostasis leading to aberrant initiation of various cell death pathways. TRPM2-mediated cell death thus emerges as an important mechanism in the pathogenesis of conditions including ischemic stroke, neurodegenerative diseases, cardiovascular diseases, diabetes, pancreatitis, chronic kidney disease, liver damage and neurovascular injury. These findings raise the exciting perspective of targeting the TRPM2 channel as a novel therapeutic strategy to treat such oxidative stress-associated diseases. © 2020 The Author(s)}, keywords = {exposure; review; human; diabetes mellitus; priority journal; nonhuman; brain ischemia; nerve cell; DISEASES; PROTEIN FUNCTION; hydrogen peroxide; vascular disease; cardiovascular disease; reactive oxygen metabolite; Parkinson disease; endothelium cell; kidney cell; liver injury; Cell Death; Cell Death; Alzheimer disease; Acute pancreatitis; protein structure; acute kidney failure; calcium homeostasis; 1,2,3,6 tetrahydro 1 methyl 4 phenylpyridine; pancreas cell; cardiac muscle cell; myocardial ischemia reperfusion injury; transient receptor potential channel M2; pericyte; TRPM2 channel; zinc homeostasis; cerebral ischemia reperfusion injury; Oxidative stress; Oxidative stress; Ca2+ and Zn2+ homeostasis}, year = {2020}, eissn = {2213-2317} } @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: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: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:30749323, title = {Structural and Evolutionary Insights Point to Allosteric Regulation of TRP Ion Channels}, url = {https://m2.mtmt.hu/api/publication/30749323}, author = {Hilton, Jacob K. and Kim, Minjoo and Van Horn, Wade D.}, doi = {10.1021/acs.accounts.9b00075}, journal-iso = {ACCOUNTS CHEM RES}, journal = {ACCOUNTS OF CHEMICAL RESEARCH}, volume = {52}, unique-id = {30749323}, issn = {0001-4842}, abstract = {The familiar pungent taste of spicy food, the refreshing taste of mint, and many other physiological phenomena are mediated by transient receptor potential (TRP) ion channels. TRP channels are a superfamily of ion channels that are sensitive to diverse chemical and physical stimuli and play diverse roles in biology. In addition to chemical regulation, some family members also sense common physical stimuli, such as temperature or pressure. Since their discovery and cloning in the 1990s and 2000s, understanding the molecular mechanisms governing TRP channel function and polymodal regulation has been a consistent but challenging goal. Until recently, a general lack of high-resolution TRP channel structures had significantly limited a molecular understanding of their function.In the past few years, a flood of TRP channel structures have been released, made possible primarily by advances in cryo-electron microscopy (cryo-EM). The boon of many structures has unleashed unparalleled insight into TRP channel architecture. Substantive comparative studies between TRP structures provide snapshots of distinct states such as ligand-free, stabilized by chemical agonists, or antagonists, partially illuminating how a given channel opens and closes. However, the now similar to 75 TRP channel structures have ushered in surprising outcomes, including a lack of an apparent general mechanism underlying channel opening and closing among family members. Similarly, the structures reveal a surprising diversity in which chemical ligands bind TRP channels.Several TRP channels are activated by temperature changes in addition to ligand binding. Unraveling mechanisms of thermosensation has proven an elusive challenge to the field. Although some studies point to thermosensitive domains in the transmembrane region of the channels, results have sometimes been contradictory and difficult to interpret; in some cases, a domain that proves essential for thermal sensitivity in one context can be entirely removed from the channel without affecting thermosensation in another context. These results are not amenable to simple interpretations and point to allosteric networks of regulation within the channel structure.TRP channels have evolved to be fine-tuned for the needs of a species in its environmental niche, a fact that has been both a benefit and burden in unlocking their molecular features. Functional evolutionary divergence has presented challenges for studying TRP channels, as orthologs from different species can give conflicting experimental results. However, this diversity can also be examined comparatively to decipher the basis for functional differences. As with structural biology, untangling the similarities and differences resulting from evolutionary pressure between species has been a rich source of data guiding the field. This Account will contextualize the existing biochemical and functional data with an eye to evolutionary data and couple these insights with emerging structural biology to better understand the molecular mechanisms behind chemical and physical regulation of TRP channels.}, year = {2019}, eissn = {1520-4898}, pages = {1643-1652} } @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: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: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:27589469, title = {TRPM2: a candidate therapeutic target for treating neurological diseases}, url = {https://m2.mtmt.hu/api/publication/27589469}, author = {Belrose, Jillian Corinne and Jackson, Michael Frederick}, doi = {10.1038/aps.2018.31}, journal-iso = {ACTA PHARMACOL SIN}, journal = {ACTA PHARMACOLOGICA SINICA}, volume = {39}, unique-id = {27589469}, issn = {1671-4083}, year = {2018}, eissn = {1745-7254}, pages = {722-732} } @article{MTMT:30538832, title = {Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium}, url = {https://m2.mtmt.hu/api/publication/30538832}, author = {Huang, Yihe and Winkler, Paige A. and Sun, Weinan and Lu, Wei and Du, Juan}, doi = {10.1038/s41586-018-0558-4}, journal-iso = {NATURE}, journal = {NATURE}, volume = {562}, unique-id = {30538832}, issn = {0028-0836}, abstract = {Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable, non-selective cation channel that has an essential role in diverse physiological processes such as core body temperature regulation, immune response and apoptosis(1-4). TRPM2 is polymodal and can be activated by a wide range of stimuli(1-7), including temperature, oxidative stress and NAD(+)-related metabolites such as ADP-ribose (ADPR). Its activation results in both Ca2+ entry across the plasma membrane and Ca2+ release from lysosomes(8), and has been linked to diseases such as ischaemia-reperfusion injury, bipolar disorder and Alzheimer's disease(9-11). Here we report the cryo-electron microscopy structures of the zebrafish TRPM2 in the apo resting (closed) state and in the ADPR/Ca2+-bound active (open) state, in which the characteristic NUDT9-H domains hang underneath the MHR1/2 domain. We identify an ADPR-binding site located in the bi-lobed structure of the MHR1/2 domain. Our results provide an insight into the mechanism of activation of the TRPM channel family and define a framework for the development of therapeutic agents to treat neurodegenerative diseases and temperature-related pathological conditions.}, year = {2018}, eissn = {1476-4687}, pages = {145-+} } @article{MTMT:27692935, title = {Oxidative stress promotes redistribution of TRPM2 channels to the plasma membrane in hepatocytes}, url = {https://m2.mtmt.hu/api/publication/27692935}, author = {Kheradpezhouh, E and Zhou, FH and Barritt, GJ and Rychkov, GY}, doi = {10.1016/j.bbrc.2018.07.132}, journal-iso = {BIOCHEM BIOPH RES CO}, journal = {BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS}, volume = {503}, unique-id = {27692935}, issn = {0006-291X}, year = {2018}, eissn = {1090-2104}, pages = {1891-1896} } @article{MTMT:27589544, title = {TRPM2 and warmth sensation}, url = {https://m2.mtmt.hu/api/publication/27589544}, author = {Tan, Chun-Hsiang and McNaughton, Peter A}, doi = {10.1007/s00424-018-2139-7}, journal-iso = {PFLUG ARCH EUR J PHY}, journal = {PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY}, volume = {470}, unique-id = {27589544}, issn = {0031-6768}, year = {2018}, eissn = {1432-2013}, pages = {787-798} } @article{MTMT:30519709, title = {Structures and gating mechanism of human TRPM2}, url = {https://m2.mtmt.hu/api/publication/30519709}, author = {Wang, Longfei and Fu, Tian-Min and Zhou, Yiming and Xia, Shiyu and Greka, Anna and Wu, Hao}, doi = {10.1126/science.aav4809}, journal-iso = {SCIENCE}, journal = {SCIENCE}, volume = {362}, unique-id = {30519709}, issn = {0036-8075}, abstract = {Transient receptor potential (TRP) melastatin 2 (TRPM2) is a cation channel associated with numerous diseases. It has a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding adenosine diphosphate (ADP) ribose (ADPR), and both ADPR and calcium (Ca2+) are required for TRPM2 activation. Here we report cryo electron microscopy structures of human TRPM2 alone, with ADPR, and with ADPR and Ca2+. NUDT9H forms both intra-and intersubunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the intersubunit interaction. The binding of Ca2+ further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening. These findings explain the molecular mechanism of concerted TRPM2 gating by ADPR and Ca2+ and provide insights into the gating mechanism of other TRP channels.}, year = {2018}, eissn = {1095-9203}, orcid-numbers = {Wang, Longfei/0000-0002-7788-2123; Zhou, Yiming/0000-0002-2109-4320; Xia, Shiyu/0000-0001-9024-0689} } @{MTMT:30642562, title = {Redox-Sensitive TRP Channels: TRPA1 and TRPM2}, url = {https://m2.mtmt.hu/api/publication/30642562}, author = {Kashio, Makiko and Tominaga, Makoto}, booktitle = {Redox}, doi = {10.5772/intechopen.69202}, unique-id = {30642562}, year = {2017}, pages = {online} } @article{MTMT:27095257, title = {The TRPM2 channel: A thermo-sensitive metabolic sensor}, url = {https://m2.mtmt.hu/api/publication/27095257}, author = {Kashio, Makiko and Tominaga, Makoto}, doi = {10.1080/19336950.2017.1344801}, journal-iso = {CHANNELS}, journal = {CHANNELS}, volume = {11}, unique-id = {27095257}, issn = {1933-6950}, year = {2017}, eissn = {1933-6969}, pages = {426-433} } @article{MTMT:27095255, title = {Different Principles of ADP-Ribose-Mediated Activation and Opposite Roles of the NUDT9 Homology Domain in the TRPM2 Orthologs of Man and Sea Anemone}, url = {https://m2.mtmt.hu/api/publication/27095255}, author = {Kuehn, Frank and Kuehn, Cornelia and Lueckhoff, Andreas}, doi = {10.3389/fphys.2017.00879}, journal-iso = {FRONT PHYSIOL}, journal = {FRONTIERS IN PHYSIOLOGY}, volume = {8}, unique-id = {27095255}, year = {2017}, eissn = {1664-042X} } @article{MTMT:26932128, title = {Modulation of activation and inactivation by Ca2+ and 2-APB in the pore of an archetypal TRPM channel from Nematostella vectensis}, url = {https://m2.mtmt.hu/api/publication/26932128}, author = {Kuehn, Frank J P and Mathis, Winking and Cornelia, Kuehn and Hoffmann, Daniel C and Lueckhoff, Andreas}, doi = {10.1038/s41598-017-07652-4}, journal-iso = {SCI REP}, journal = {SCIENTIFIC REPORTS}, volume = {7}, unique-id = {26932128}, issn = {2045-2322}, year = {2017}, eissn = {2045-2322} } @article{MTMT:30642422, title = {New insights into the interaction between ADP-ribose and human TRPM2 channel}, url = {https://m2.mtmt.hu/api/publication/30642422}, author = {Kühn, Frank JP}, doi = {10.21037/biotarget.2017.10.01}, journal = {Biotarget}, volume = {2017}, unique-id = {30642422}, issn = {2522-669X}, year = {2017} } @article{MTMT:26764281, title = {Redox regulation of transient receptor potential channels in the endothelium}, url = {https://m2.mtmt.hu/api/publication/26764281}, author = {Pires, Paulo Wagner and Earley, Scott}, doi = {10.1111/micc.12329}, journal-iso = {MICROCIRCULATION}, journal = {MICROCIRCULATION}, volume = {24}, unique-id = {26764281}, issn = {1073-9688}, year = {2017}, eissn = {1549-8719} } @article{MTMT:26622637, title = {The evolution of function within the Nudix homology clan}, url = {https://m2.mtmt.hu/api/publication/26622637}, author = {Srouji, JR and Xu, A and Park, A and Kirsch, JF and Brenner, SE}, doi = {10.1002/prot.25223}, journal-iso = {PROTEINS}, journal = {PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS}, volume = {85}, unique-id = {26622637}, issn = {0887-3585}, year = {2017}, eissn = {1097-0134}, pages = {775-811} } @article{MTMT:26497564, title = {Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2}, url = {https://m2.mtmt.hu/api/publication/26497564}, author = {Yu, P and Xue, X and Zhang, J and Hu, X and Wu, Y and Jiang, L-H and Jin, H and Luo, J and Zhang, L and Liu, Z and Yang, W}, doi = {10.1085/jgp.201611675}, journal-iso = {J GEN PHYSIOL}, journal = {JOURNAL OF GENERAL PHYSIOLOGY}, volume = {149}, unique-id = {26497564}, issn = {0022-1295}, year = {2017}, eissn = {1540-7748}, pages = {219-235} } @article{MTMT:27095254, title = {TRPM channels as potential therapeutic targets against pro-inflammatory diseases}, url = {https://m2.mtmt.hu/api/publication/27095254}, author = {Zierler, Susanna and Hampe, Sarah and Nadolni, Wiebke}, doi = {10.1016/j.ceca.2017.05.002}, journal-iso = {CELL CALCIUM}, journal = {CELL CALCIUM}, volume = {67}, unique-id = {27095254}, issn = {0143-4160}, year = {2017}, eissn = {1532-1991}, pages = {105-115}, orcid-numbers = {Zierler, Susanna/0000-0002-4684-0385} }