@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:34235533, title = {The fallacy of functional nomenclature in the kingdom of biological multifunctionality: physiological and evolutionary considerations on ion channels}, url = {https://m2.mtmt.hu/api/publication/34235533}, author = {Munaron, Luca and Chinigo, Giorgia and Scarpellino, Giorgia and Ruffinatti, Federico Alessandro}, doi = {10.1113/JP284422}, journal-iso = {J PHYSIOL-LONDON}, journal = {JOURNAL OF PHYSIOLOGY-LONDON}, unique-id = {34235533}, issn = {0022-3751}, abstract = {Living organisms are multiscale complex systems that have evolved high degrees of multifunctionality and redundancy in the structure-function relationship. A number of factors, only in part determined genetically, affect the jobs of proteins. The overall structural organization confers unique molecular properties that provide the potential to perform a pattern of activities, some of which are co-opted by specific environments. The variety of multifunctional proteins is expanding, but most cases are handled individually and according to the still dominant 'one structure-one function' approach, which relies on the attribution of canonical names typically referring to the first task identified for a given protein. The present topical review focuses on the multifunctionality of ion channels as a paradigmatic example. Mounting evidence reports the ability of many ion channels (including members of voltage-dependent, ligand-gated and transient receptor potential families) to exert biological effects independently of their ion conductivity. 'Functionally based' nomenclature (the practice of naming a protein or family of proteins based on a single purpose) is a conceptual bias for three main reasons: (i) it increases the amount of ambiguity, deceiving our understanding of the multiple contributions of biomolecules that is the heart of the complexity; (ii) it is in stark contrast to protein evolution dynamics, largely based on multidomain arrangement; and (iii) it overlooks the crucial role played by the microenvironment in adjusting the actions of cell structures and in tuning protein isoform diversity to accomplish adaptational requirements. Biological information in protein physiology is distributed among different entwined layers working as the primary 'locus' of natural selection and of evolutionary constraints.imageAbstract figure legend Different features underlying the multifunctional nature of ion channels. image}, keywords = {ION CHANNELS; multifunctionality; Evolutionary physiology; Cellular physiology; functional names}, year = {2023}, eissn = {1469-7793} } @article{MTMT:34487828, title = {Interaction of Calmodulin with TRPM: An Initiator of Channel Modulation}, url = {https://m2.mtmt.hu/api/publication/34487828}, author = {Vydra Bousova, Kristyna and Zouharova, Monika and Jiraskova, Katerina and Vetyskova, Veronika}, doi = {10.3390/ijms242015162}, journal-iso = {INT J MOL SCI}, journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, volume = {24}, unique-id = {34487828}, issn = {1661-6596}, abstract = {Transient receptor potential melastatin (TRPM) channels, a subfamily of the TRP superfamily, constitute a diverse group of ion channels involved in mediating crucial cellular processes like calcium homeostasis. These channels exhibit complex regulation, and one of the key regulatory mechanisms involves their interaction with calmodulin (CaM), a cytosol ubiquitous calcium-binding protein. The association between TRPM channels and CaM relies on the presence of specific CaM-binding domains in the channel structure. Upon CaM binding, the channel undergoes direct and/or allosteric structural changes and triggers down- or up-stream signaling pathways. According to current knowledge, ion channel members TRPM2, TRPM3, TRPM4, and TRPM6 are directly modulated by CaM, resulting in their activation or inhibition. This review specifically focuses on the interplay between TRPM channels and CaM and summarizes the current known effects of CaM interactions and modulations on TRPM channels in cellular physiology.}, year = {2023}, eissn = {1422-0067}, orcid-numbers = {Vydra Bousova, Kristyna/0000-0001-9030-3811; Zouharova, Monika/0000-0002-2254-6480; Jiraskova, Katerina/0000-0001-8462-6358; Vetyskova, Veronika/0000-0002-6740-4814} } @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: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:32372253, title = {Role of TRP ion channels in cerebral circulation and neurovascular communication}, url = {https://m2.mtmt.hu/api/publication/32372253}, author = {Kuppusamy, Maniselvan and Ottolini, Matteo and Sonkusare, Swapnil K.}, doi = {10.1016/j.neulet.2021.136258}, journal-iso = {NEUROSCI LETT}, journal = {NEUROSCIENCE LETTERS}, volume = {765}, unique-id = {32372253}, issn = {0304-3940}, abstract = {The dynamic regulation of blood flow is essential for meeting the high metabolic demands of the brain and maintaining brain function. Cerebral blood flow is regulated primarily by 1) the intrinsic mechanisms that determine vascular contractility and 2) signals from neurons and astrocytes that alter vascular contractility. Stimuli from neurons and astrocytes can also initiate a signaling cascade in the brain capillary endothelium to increase regional blood flow. Recent studies provide evidence that TRP channels in endothelial cells, smooth muscle cells, neurons, astrocytes, and perivascular nerves control cerebrovascular contractility and cerebral blood flow. TRP channels exert their functional effects either through cell membrane depolarization or by serving as a Ca2+ influx pathway. Endothelial cells and astrocytes also maintain the integrity of the blood-brain barrier. Both endothelial cells and astrocytes express TRP channels, and an increase in endothelial TRP channel activity has been linked with a disrupted endothelial barrier function. Therefore, TRP channels can play a potentially important role in regulating blood-brain barrier integrity. Here, we review the regulation of cerebrovascular contractility by TRP channels under healthy and disease conditions and their potential roles in maintaining blood-brain barrier function.}, keywords = {Blood-Brain Barrier; TRP CHANNELS; cerebral blood flow; Neurovascular coupling; Cerebral microcirculation}, year = {2021}, eissn = {1872-7972} } @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: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: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: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: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: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: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: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: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:26355293, title = {Chemical activation of sensory TRP channels}, url = {https://m2.mtmt.hu/api/publication/26355293}, author = {Boonen, B and Startek, JB and Talavera, K}, booktitle = {Taste and Smell}, doi = {10.1007/7355_2015_98}, unique-id = {26355293}, year = {2017}, pages = {73-114} } @{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:26578581, title = {TRPM2: a potential drug target to retard oxidative stress}, url = {https://m2.mtmt.hu/api/publication/26578581}, author = {Li, Jun and Gao, Yunling and Bao, Xianying and Li, Fengna and Yao, Wei and Feng, Zemeng and Yin, Yulong}, doi = {10.2741/4551}, journal-iso = {FRONT BIOSCI-LANDMARK}, journal = {FRONTIERS IN BIOSCIENCE-LANDMARK}, volume = {22}, unique-id = {26578581}, issn = {2768-6701}, year = {2017}, eissn = {2768-6698}, pages = {1427-1438} } @mastersthesis{MTMT:30638059, title = {Synthese funktionalisierter Zuckernucleotide und deren Anwendbarkeit als biologische Tools}, url = {https://m2.mtmt.hu/api/publication/30638059}, author = {Pahnke, Katharina}, unique-id = {30638059}, year = {2017} } @misc{MTMT:30638060, title = {The role of spinal TRPV1 receptors in nociceptive signalling and the modulatory effect of chemokine CCL2 and µ-opioid receptor agonists}, url = {https://m2.mtmt.hu/api/publication/30638060}, author = {Šulcová, Dominika}, unique-id = {30638060}, year = {2017} } @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} } @article{MTMT:25784873, title = {A Synopsis on the Linkage Between Age-Related Dementias and Vascular Disorders}, url = {https://m2.mtmt.hu/api/publication/25784873}, author = {Chibber, Sandesh and Alexiou, Athanasios and Alama, Mohammed Nabil and Emilio, Barreto George and Aliev, Gjumrakch and Ashraf, Ghulam Mohammad}, doi = {10.2174/1871527315666160202121809}, journal-iso = {CNS NEUROL DISORD-DR}, journal = {CNS & NEUROLOGICAL DISORDERS-DRUG TARGETS}, volume = {15}, unique-id = {25784873}, issn = {1871-5273}, year = {2016}, eissn = {1996-3181}, pages = {250-258} } @article{MTMT:3105008, title = {The proposed channel-enzyme transient receptor potential melastatin 2 does not possess ADP ribose hydrolase activity}, url = {https://m2.mtmt.hu/api/publication/3105008}, author = {Iordanov, Iordan and Mihályi, Csaba and Tóth, Balázs and Csanády, László}, doi = {10.7554/eLife.17600}, journal-iso = {ELIFE}, journal = {ELIFE}, volume = {5}, unique-id = {3105008}, issn = {2050-084X}, year = {2016}, eissn = {2050-084X}, orcid-numbers = {Iordanov, Iordan/0000-0001-8251-5857; Mihályi, Csaba/0000-0001-7536-3066; Tóth, Balázs/0000-0002-1257-2597; Csanády, László/0000-0002-6547-5889} } @article{MTMT:26029746, title = {ADP-Ribose Activates the TRPM2 Channel from the Sea Anemone Nematostella vectensis Independently of the NUDT9H Domain}, url = {https://m2.mtmt.hu/api/publication/26029746}, author = {Kuehn, Frank J P and Kuehn, Cornelia and Winking, Mathis and Hoffmann, Daniel C and Lueckhoff, Andreas}, doi = {10.1371/journal.pone.0158060}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {11}, unique-id = {26029746}, issn = {1932-6203}, year = {2016}, eissn = {1932-6203} } @article{MTMT:26178279, title = {Pathological role of transient receptor potential melastatin member 2 channel in neurodegenerative diseases and Alzheimer disease}, url = {https://m2.mtmt.hu/api/publication/26178279}, author = {Li, F-Y and Wong, R and Turlova, E and Sun, H-S}, doi = {10.3867/j.issn.1000-3002.2016.06.005}, journal-iso = {CHINESE J PHARM TOXICOL}, journal = {CHINESE JOURNAL OF PHARMACOLOGY AND TOXICOLOGY / ZHONG GUO YAO LI XUE YU DU LI XUE ZA ZHI}, volume = {30}, unique-id = {26178279}, issn = {1000-3002}, year = {2016}, pages = {656-666} } @article{MTMT:26170511, title = {Sensing of redox status by TRP channels}, url = {https://m2.mtmt.hu/api/publication/26170511}, author = {Ogawa, Nozomi and Kurokawa, Tatsuki and Mori, Yasuo}, doi = {10.1016/j.ceca.2016.02.009}, journal-iso = {CELL CALCIUM}, journal = {CELL CALCIUM}, volume = {60}, unique-id = {26170511}, issn = {0143-4160}, year = {2016}, eissn = {1532-1991}, pages = {115-122} } @article{MTMT:25361600, title = {Novel Alleles of gon-2, a C-elegans Ortholog of Mammalian TRPM6 and TRPM7, Obtained by Genetic Reversion Screens}, url = {https://m2.mtmt.hu/api/publication/25361600}, author = {Lambie, Eric J and Bruce, Robert D III and Zielich, Jeffrey and Yuen, Sonia N}, doi = {10.1371/journal.pone.0143445}, journal-iso = {PLOS ONE}, journal = {PLOS ONE}, volume = {10}, unique-id = {25361600}, issn = {1932-6203}, year = {2015}, eissn = {1932-6203} } @article{MTMT:25361599, title = {Activators of TRPM2: Getting it right}, url = {https://m2.mtmt.hu/api/publication/25361599}, author = {Rosenbaum, Tamara}, doi = {10.1085/jgp.201511405}, journal-iso = {J GEN PHYSIOL}, journal = {JOURNAL OF GENERAL PHYSIOLOGY}, volume = {145}, unique-id = {25361599}, issn = {0022-1295}, year = {2015}, eissn = {1540-7748}, pages = {485-487} } @article{MTMT:2949645, title = {Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist ADP-ribose-2'-phosphate}, url = {https://m2.mtmt.hu/api/publication/2949645}, author = {Tóth, Balázs and Iordanov, Iordan and Csanády, László}, doi = {10.1085/jgp.201511377}, journal-iso = {J GEN PHYSIOL}, journal = {JOURNAL OF GENERAL PHYSIOLOGY}, volume = {145}, unique-id = {2949645}, issn = {0022-1295}, abstract = {Transient receptor potential melastatin 2 (TRPM2), a Ca(2+)-permeable cation channel implicated in postischemic neuronal cell death, leukocyte activation, and insulin secretion, is activated by intracellular ADP ribose (ADPR). In addition, the pyridine dinucleotides nicotinamide-adenine-dinucleotide (NAD), nicotinic acid-adenine-dinucleotide (NAAD), and NAAD-2'-phosphate (NAADP) have been shown to activate TRPM2, or to enhance its activation by ADPR, when dialyzed into cells. The precise subset of nucleotides that act directly on the TRPM2 protein, however, is unknown. Here, we use a heterologously expressed, affinity-purified-specific ADPR hydrolase to purify commercial preparations of pyridine dinucleotides from substantial contaminations by ADPR or ADPR-2'-phosphate (ADPRP). Direct application of purified NAD, NAAD, or NAADP to the cytosolic face of TRPM2 channels in inside-out patches demonstrated that none of them stimulates gating, or affects channel activation by ADPR, indicating that none of these dinucleotides directly binds to TRPM2. Instead, our experiments identify for the first time ADPRP as a true direct TRPM2 agonist of potential biological interest.}, year = {2015}, eissn = {1540-7748}, pages = {419-430}, orcid-numbers = {Tóth, Balázs/0000-0002-1257-2597; Iordanov, Iordan/0000-0001-8251-5857; Csanády, László/0000-0002-6547-5889} }