TY - JOUR AU - Szöllősi, András AU - Almássy, János TI - Functional characterization of the transient receptor potential melastatin 2 (TRPM2) cation channel from Nematostella vectensis reconstituted into lipid bilayer JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 13 PY - 2023 IS - 1 PG - 10 SN - 2045-2322 DO - 10.1038/s41598-023-38640-6 UR - https://m2.mtmt.hu/api/publication/34064647 ID - 34064647 N1 - Department of Biochemistry, Semmelweis University, Tuzolto u. 37-47, Budapest, 1094, Hungary Department of Physiology, Semmelweis University, Tuzolto u. 37-47, Budapest, 1094, Hungary ELKH-SE Ion Channel Research Group, Semmelweis University, Tuzolto u. 37-47, Budapest, 1094, Hungary HCEMM-SE Molecular Channelopathies Research Group, Semmelweis University, Tuzolto u. 37-47, Budapest, 1094, Hungary Export Date: 4 September 2023 Correspondence Address: Szollosi, A.; Department of Biochemistry, Tuzolto u. 37-47, Hungary; email: szollo5@gmail.com Chemicals/CAS: adenosine diphosphate ribose, 20762-30-5; calcium, 7440-70-2, 14092-94-5; Adenosine Diphosphate Ribose; Calcium; Cations; Lipid Bilayers; TRPM Cation Channels Funding details: 739593 Funding details: Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, NKFIA, KKP 144199 Funding text 1: This work was supported by Semmelweis Science and Innovation Fund STIA_18_M; EU Horizon 2020 Research and Innovation Program grant 739593 and National Research, Development and Innovation Fund grant KKP 144199. We thank László Csanády for funding and thorough reading and comments on the manuscript. We thank Balázs Tóth for help with poly- l -lysine measurements and stimulating discussions. AB - Transient receptor potential melastatin 2 (TRPM2) cation channel activity is required for insulin secretion, immune cell activation and body heat control. Channel activation upon oxidative stress is involved in the pathology of stroke and neurodegenerative disorders. Cytosolic Ca 2+ , ADP-ribose (ADPR) and phosphatidylinositol-4,5-bisphosphate (PIP 2 ) are the obligate activators of the channel. Several TRPM2 cryo-EM structures have been resolved to date, yet functionality of the purified protein has not been tested. Here we reconstituted overexpressed and purified TRPM2 from Nematostella vectensis (nvTRPM2) into lipid bilayers and found that the protein is fully functional. Consistent with the observations in native membranes, nvTRPM2 in lipid bilayers is co-activated by cytosolic Ca 2+ and either ADPR or ADPR-2′-phosphate (ADPRP). The physiological metabolite ADPRP has a higher apparent affinity than ADPR. In lipid bilayers nvTRPM2 displays a large linear unitary conductance, its open probability (P o ) shows little voltage dependence and is stable over several minutes. P o is high without addition of exogenous PIP 2 , but is largely blunted by treatment with poly- l -Lysine, a polycation that masks PIP 2 headgroups. These results indicate that PIP 2 or some other activating phosphoinositol lipid co-purifies with nvTRPM2, suggesting a high PIP 2 binding affinity of nvTRPM2 under physiological conditions. LA - English DB - MTMT ER - TY - JOUR AU - Bartók, Ádám AU - Csanády, László TI - Dual amplification strategy turns TRPM2 channels into supersensitive central heat detectors JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA J2 - P NATL ACAD SCI USA VL - 119 PY - 2022 IS - 48 PG - 11 SN - 0027-8424 DO - 10.1073/pnas.2212378119 UR - https://m2.mtmt.hu/api/publication/33262968 ID - 33262968 N1 - Hungarian Centre of Excellence for Molecular Medicine-Semmelweis Egyetem (HCEMM-SE), Molecular Channelopathies Research Group, Semmelweis University, Budapest, H-1094, Hungary Magyar Tudományos Akadémia-Semmelweis Egyetem (MTA-SE), Ion Channel Research Group, Semmelweis University, Budapest, H-1094, Hungary Department of Biochemistry, Semmelweis University, Budapest, H-1094, Hungary Cited By :3 Export Date: 4 September 2023 CODEN: PNASA Correspondence Address: Csanády, L.; Hungarian Centre of Excellence for Molecular Medicine-Semmelweis Egyetem (HCEMM-SE), Hungary; email: csanady.laszlo@med.semmelweis-univ.hu Chemicals/CAS: adenosine diphosphate ribose, 20762-30-5; calcium ion, 14127-61-8; hydrogen peroxide, 7722-84-1; calcium, 7440-70-2, 14092-94-5; Adenosine Diphosphate Ribose; Calcium; Hydrogen Peroxide; TRPM Cation Channels Funding details: 739593 Funding details: GINOP-2.3.2-15-2016-00051 Funding details: ÚNKP-20-5-SE-6, ÚNKP-21-5-SE-10 Funding details: Magyar Tudományos Akadémia, MTA, BO/00103/20, LP2017-14/2017 Funding details: Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, NKFIH Funding text 1: We thank Beáta Töröcsik for subcloning T5L-TRPM2 into pcDNA3, Iordan Iordanov for providing purified nvNUDT9H, and Katalin Zboray (Agricultural Institute, Centre for Agricultural Research, Martonvásár, Hungary) for providing the stable T5L TRPM2 cell line (Economic Development and Innovation Operational Programme (GINOP-2.3.2-15-2016-00051) of the National Research, Development and Innovation Office). Support was provided by EU Horizon 2020 Research and Innovation Program grant 739593 and MTA Lendület grant LP2017-14/2017 to L.C. and a New National Excellence Program (ÚNKP) award of the Ministry of Human Capacities of Hungary to Semmelweis University. Á.B. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00103/20) and the New National Excellence Program (ÚNKP) Bolyai+ scholarship of the Ministry of Human Capacities of Hungary (ÚNKP-20-5-SE-6 and ÚNKP-21-5-SE-10). Funding text 2: ACKNOWLEDGMENTS. We thank Beáta Töröcsik for subcloning T5L-TRPM2 into pcDNA3, Iordan Iordanov for providing purified nvNUDT9H, and Katalin Zboray (Agricultural Institute, Centre for Agricultural Research, Martonvásár, Hungary) for providing the stableT5LTRPM2 cell line (Economic Development and Innovation Operational Programme (GINOP-2.3.2-15-2016-00051) of the National Research, Development and Innovation Office). Support was provided by EU Horizon 2020 Research and Innovation Program grant 739593 and MTA Lendület grant LP2017-14/2017 to L.C. and a New National Excellence Program (ÚNKP) award of the Ministry of Human Capacities of Hungary to Semmelweis University. Á.B. was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences (BO/00103/20) and the New National Excellence Program (ÚNKP) Bolyai+ scholarship of the Ministry of Human Capacities of Hungary (ÚNKP-20-5-SE-6 and ÚNKP-21-5-SE-10). AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Riekehr, W.M. AU - Sander, S. AU - Pick, J. AU - Tidow, H. AU - Bauche, A. AU - Guse, A.H. AU - Fliegert, R. TI - cADPR Does Not Activate TRPM2 JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 6 SN - 1661-6596 DO - 10.3390/ijms23063163 UR - https://m2.mtmt.hu/api/publication/32793002 ID - 32793002 N1 - The Calcium Signalling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf, Hamburg, 20246, Germany The Hamburg Advanced Research Center for Bioorganic Chemistry (HARBOR) & Department of Chemistry, Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, 22761, Germany Export Date: 25 April 2022 Correspondence Address: Fliegert, R.; The Calcium Signalling Group, Germany; email: r.fliegert@uke.de Funding details: Deutsche Forschungsgemeinschaft, DFG, 335447717, SFB 1328 Funding text 1: Funding: This work was supported by the Deutsche Forschungsgemeinschaft (DFG) grant number 335447717; SFB 1328, projects A01 to A.H.G. and A05 to H.T. and R.F., J.P. had a scholarship from the SFB1328 Integrated Research Training Group (IRTG). AB - cADPR is a second messenger that releases Ca2+ from intracellular stores via the ryanodine receptor. Over more than 15 years, it has been controversially discussed whether cADPR also contributes to the activation of the nucleotide-gated cation channel TRPM2. While some groups have observed activation of TRPM2 by cADPR alone or in synergy with ADPR, sometimes only at 37◦ C, others have argued that this is due to the contamination of cADPR by ADPR. The identification of a novel nucleotide-binding site in the N-terminus of TRPM2 that binds ADPR in a horseshoe-like conformation resembling cADPR as well as the cADPR antagonist 8-Br-cADPR, and another report that demonstrates activation of TRPM2 by binding of cADPR to the NUDT9H domain raised the question again and led us to revisit the topic. Here we show that (i) the N-terminal MHR1/2 domain and the C-terminal NUDT9H domain are required for activation of human TRPM2 by ADPR and 2′-deoxy-ADPR (2dADPR), (ii) that pure cADPR does not activate TRPM2 under a variety of conditions that have previously been shown to result in channel activation, (iii) the cADPR antagonist 8-Br-cADPR also inhibits activation of TRPM2 by ADPR, and (iv) cADPR does not bind to the MHR1/2 domain of TRPM2 while ADPR does. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. LA - English DB - MTMT ER - TY - JOUR AU - Sander, S. AU - Pick, J. AU - Gattkowski, E. AU - Fliegert, R. AU - Tidow, H. TI - The crystal structure of TRPM2 MHR1/2 domain reveals a conserved Zn2+-binding domain essential for structural integrity and channel activity JF - PROTEIN SCIENCE J2 - PROTEIN SCI VL - 31 PY - 2022 IS - 6 SN - 0961-8368 DO - 10.1002/pro.4320 UR - https://m2.mtmt.hu/api/publication/33063833 ID - 33063833 N1 - Hamburg Advanced Research Centre for Bioorganic Chemistry (HARBOR) & Department of Chemistry, Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany The Calcium Signaling Group, Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Export Date: 24 August 2022 CODEN: PRCIE Correspondence Address: Tidow, H.; Hamburg Advanced Research Centre for Bioorganic Chemistry (HARBOR) & Department of Chemistry, Germany; email: tidow@chemie.uni-hamburg.de Chemicals/CAS: adenosine diphosphate ribose, 20762-30-5; calcium, 7440-70-2, 14092-94-5; zinc, 7440-66-6, 14378-32-6; Adenosine Diphosphate Ribose; Calcium; TRPM Cation Channels; Zinc Funding details: European Molecular Biology Laboratory, EMBL Funding details: Deutsche Forschungsgemeinschaft, DFG, SFB1328 Funding text 1: The authors are grateful to the staff at beamlines P14 and P13 (EMBL, Hamburg) and thank members of the Tidow and Fliegert labs for helpful discussions. The authors acknowledge access to the Sample Preparation and Characterization (SPC) Facility of EMBL, Hamburg. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (SFB1328, project A05 to Henning Tidow and Ralf Fliegert). Open Access funding enabled and organized by Projekt DEAL. Funding text 2: The authors are grateful to the staff at beamlines P14 and P13 (EMBL, Hamburg) and thank members of the Tidow and Fliegert labs for helpful discussions. The authors acknowledge access to the Sample Preparation and Characterization (SPC) Facility of EMBL, Hamburg. This work was supported by the Deutsche Forschungsgemeinschaft (DFG) (SFB1328, project A05 to Henning Tidow and Ralf Fliegert). Open Access funding enabled and organized by Projekt DEAL. AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Sousza, Bomfim G.H. AU - Niemeyer, B.A. AU - Lacruz, R.S. AU - Lis, A. TI - On the Connections between TRPM Channels and SOCE JF - CELLS J2 - CELLS-BASEL VL - 11 PY - 2022 IS - 7 SN - 2073-4409 DO - 10.3390/cells11071190 UR - https://m2.mtmt.hu/api/publication/32793001 ID - 32793001 N1 - Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, United States Department of Molecular Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, 66421, Germany Department of Biophysics, Center for Integrative Physiology and Molecular Medicine, School of Medicine, Saarland University, Homburg, 66421, Germany Export Date: 25 April 2022 Correspondence Address: Lacruz, R.S.; Department of Molecular Pathobiology, United States; email: rsl10@nyu.edu Correspondence Address: Lis, A.; Department of Biophysics, Germany; email: annette.lis@uks.eu Chemicals/CAS: adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; calcium ion, 14127-61-8; cyclic GMP, 7665-99-8; Smad2 protein, 253862-89-4; calcium, 7440-70-2, 14092-94-5; Calcium; Calcium Channels; Calcium Release Activated Calcium Channels; ORAI1 Protein; Transient Receptor Potential Channels; TRPM Cation Channels Funding details: National Institute of Dental and Craniofacial Research, NIDCR, DE025639, DE027981 Funding details: Deutsche Forschungsgemeinschaft, DFG, 322900939| M04, LI 1750/4-2, SFB1027|C4, SFB894, TRR219 Funding text 1: to R.S.L. was provided by the National Institute of Dental and Craniofacial Research (NIDCR) grants DE025639, DE027981 and DE027981. Funding to B.A.N was provided by Deutsche Forschungsgemeinschaft (DFG) grants SFB1027|C4, SFB894|A2 and TRR219|322900939| M04 and to A.L. by DFG grant LI 1750/4-2. AB - Plasma membrane protein channels provide a passageway for ions to access the intracellular milieu. Rapid entry of calcium ions into cells is controlled mostly by ion channels, while Ca2+-ATPases and Ca2+ exchangers ensure that cytosolic Ca2+ levels ([Ca2+ ]cyt) are maintained at low (~100 nM) concentrations. Some channels, such as the Ca2+-release-activated Ca2+ (CRAC) channels and voltagedependent Ca2+ channels (CACNAs), are highly Ca2+-selective, while others, including the Transient Receptor Potential Melastatin (TRPM) family, have broader selectivity and are mostly permeable to monovalent and divalent cations. Activation of CRAC channels involves the coupling between ORAI1-3 channels with the endoplasmic reticulum (ER) located Ca2+ store sensor, Stromal Interaction Molecules 1-2 (STIM1/2), a pathway also termed store-operated Ca2+ entry (SOCE). The TRPM family is formed by 8 members (TRPM1-8) permeable to Mg2+, Ca2+, Zn2+ and Na+ cations, and is activated by multiple stimuli. Recent studies indicated that SOCE and TRPM structure-function are interlinked in some instances, although the molecular details of this interaction are only emerging. Here we review the role of TRPM and SOCE in Ca2+ handling and highlight the available evidence for this interaction. © 2022 by the authors. Licensee MDPI, Basel, Switzerland. LA - English DB - MTMT ER - TY - JOUR AU - Barth, D. AU - Lückhoff, A. AU - Kühn, F.J.P. TI - Species-specific regulation of trpm2 by pi(4,5)p2 via the membrane interfacial cavity JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 9 SN - 1661-6596 DO - 10.3390/ijms22094637 UR - https://m2.mtmt.hu/api/publication/32008293 ID - 32008293 N1 - Export Date: 11 May 2021 Correspondence Address: Barth, D.; Institute of Physiology, Germany; email: dbarth@ukaachen.de Funding details: Deutsche Forschungsgemeinschaft, DFG, KU Funding details: Deutsche Forschungsgemeinschaft, DFG Funding text 1: by the Deutsche Forschungsgemeinschaft (DFG, Grant KU Export Date: 13 May 2021 Correspondence Address: Barth, D.; Institute of Physiology, Germany; email: dbarth@ukaachen.de Funding details: Deutsche Forschungsgemeinschaft, DFG, KU Funding details: Deutsche Forschungsgemeinschaft, DFG Funding text 1: by the Deutsche Forschungsgemeinschaft (DFG, Grant KU Cited By :1 Export Date: 9 September 2021 Correspondence Address: Barth, D.; Institute of Physiology, Germany; email: dbarth@ukaachen.de Chemicals/CAS: phosphatidylinositol 4,5 bisphosphate, 94161-15-6; Phosphatidylinositol 4,5-Diphosphate; TRPM Cation Channels; TRPM2 protein, human Funding details: Deutsche Forschungsgemeinschaft, DFG, KU Funding text 1: by the Deutsche Forschungsgemeinschaft (DFG, Grant KU Cited By :1 Export Date: 10 September 2021 Correspondence Address: Barth, D.; Institute of Physiology, Germany; email: dbarth@ukaachen.de Chemicals/CAS: phosphatidylinositol 4,5 bisphosphate, 94161-15-6; Phosphatidylinositol 4,5-Diphosphate; TRPM Cation Channels; TRPM2 protein, human Funding details: Deutsche Forschungsgemeinschaft, DFG, KU Funding text 1: by the Deutsche Forschungsgemeinschaft (DFG, Grant KU Cited By :1 Export Date: 14 September 2021 Correspondence Address: Barth, D.; Institute of Physiology, Germany; email: dbarth@ukaachen.de Chemicals/CAS: phosphatidylinositol 4,5 bisphosphate, 94161-15-6; Phosphatidylinositol 4,5-Diphosphate; TRPM Cation Channels; TRPM2 protein, human Funding details: Deutsche Forschungsgemeinschaft, DFG, KU Funding text 1: by the Deutsche Forschungsgemeinschaft (DFG, Grant KU Cited By :1 Export Date: 15 September 2021 Correspondence Address: Barth, D.; Institute of Physiology, Germany; email: dbarth@ukaachen.de Chemicals/CAS: phosphatidylinositol 4,5 bisphosphate, 94161-15-6; Phosphatidylinositol 4,5-Diphosphate; TRPM Cation Channels; TRPM2 protein, human Funding details: Deutsche Forschungsgemeinschaft, DFG, KU Funding text 1: by the Deutsche Forschungsgemeinschaft (DFG, Grant KU AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Szöllősi, András TI - Two decades of evolution of our understanding of the transient receptor potential melastatin 2 (Trpm2) cation channel JF - LIFE-BASEL J2 - LIFE-BASEL VL - 11 PY - 2021 IS - 5 PG - 23 SN - 2075-1729 DO - 10.3390/life11050397 UR - https://m2.mtmt.hu/api/publication/32040119 ID - 32040119 N1 - Department of Medical Biochemistry, Semmelweis University, Budapest, 1085, Hungary MTA-SE Lendület Ion Channel Research Group, Semmelweis University, Budapest, 1085, Hungary HCEMM-SE Molecular Channelopathies Research Group, Semmelweis University, Budapest, 1085, Hungary Cited By :2 Export Date: 9 March 2022 Correspondence Address: Szollosi, A.; Department of Medical Biochemistry, Hungary; email: szollosi.andras@med.semmelweis-univ.hu Funding details: 739593 Funding details: LP2017-14/2017 Funding text 1: Supported by MTA Lend?let grant LP2017-14/2017 and EU Horizon 2020 Research and Innovation Program grant 739593. Funding text 2: Funding: Supported by MTA Lendület grant LP2017-14/2017 and EU Horizon 2020 Research and Innovation Program grant 739593. AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Fliegert, Ralf AU - Riekehr, Winnie M. AU - Guse, Andreas H. TI - Does Cyclic ADP-Ribose (cADPR) Activate the Non-selective Cation Channel TRPM2? JF - FRONTIERS IN IMMUNOLOGY J2 - FRONT IMMUNOL VL - 11 PY - 2020 PG - 6 SN - 1664-3224 DO - 10.3389/fimmu.2020.02018 UR - https://m2.mtmt.hu/api/publication/31697230 ID - 31697230 N1 - Export Date: 12 April 2021 Correspondence Address: Guse, A.H.; The Calcium Signalling Group, Germany; email: guse@uke.de Funding details: National Institutes of Health, NIH, P41-GM103311 Funding details: European Commission, EC, DLV-813284 Funding details: Deutsche Forschungsgemeinschaft, DFG, 335447717, SFB1328 Funding text 1: Visualization of the structures was done using UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311 (60). Funding. This work was supported by the Deutsche Forschungsgemein- schaft (DFG) (Project number 335447717; SFB1328, project A01 to AG, SFB1328, project A05 to RF). Research in the Guse/Fliegert labs is also supported by the Joachim-Herz-Foundation, the Infectophysics consortium, project 4; and EU project INTEGRATA - DLV-813284. Cited By :3 Export Date: 9 September 2021 Correspondence Address: Guse, A.H.; The Calcium Signalling Group, Germany; email: guse@uke.de Chemicals/CAS: adenosine diphosphate, 20398-34-9, 58-64-0; cyclic adenosine diphosphate ribose, 119340-53-3; calcium, 7440-70-2, 14092-94-5; Calcium; Cyclic ADP-Ribose; TRPM Cation Channels; TRPM2 protein, human Funding details: National Institutes of Health, NIH, P41-GM103311 Funding details: European Commission, EC, DLV-813284 Funding details: Deutsche Forschungsgemeinschaft, DFG, 335447717, SFB1328 Funding text 1: Visualization of the structures was done using UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311 (60). Funding. This work was supported by the Deutsche Forschungsgemein- schaft (DFG) (Project number 335447717; SFB1328, project A01 to AG, SFB1328, project A05 to RF). Research in the Guse/Fliegert labs is also supported by the Joachim-Herz-Foundation, the Infectophysics consortium, project 4; and EU project INTEGRATA - DLV-813284. AB - TRPM2 is a non-selective, Ca2+-permeable cation channel widely expressed in immune cells. It is firmly established that the channel can be activated by intracellular adenosine 5 '-diphosphoribose (ADPR). Until recent cryo-EM structures have exhibited an additional nucleotide binding site in the N-terminus of the channel, this activation was thought to occur via binding to a C-terminal domain of the channel that is highly homologous to the ADPR pyrophosphatase NudT9. Over the years it has been controversially discussed whether the Ca(2+)mobilizing second messenger cyclic ADP ribose (cADPR) might also directly activate Ca(2+)entry via TRPM2. Here we will review the status of this discussion. LA - English DB - MTMT ER - TY - JOUR AU - Himmel, Nathaniel J. AU - Cox, Daniel N. TI - Transient receptor potential channels: current perspectives on evolution, structure, function and nomenclature JF - PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES J2 - P ROY SOC B-BIOL SCI VL - 287 PY - 2020 IS - 1933 PG - 9 SN - 0962-8452 DO - 10.1098/rspb.2020.1309 UR - https://m2.mtmt.hu/api/publication/31721367 ID - 31721367 AB - The transient receptor potential superfamily of ion channels (TRP channels) is widely recognized for the roles its members play in sensory nervous systems. However, the incredible diversity within the TRP superfamily, and the wide range of sensory capacities found therein, has also allowed TRP channels to function beyond sensing an organism's external environment, and TRP channels have thus become broadly critical to (at least) animal life. TRP channels were originally discovered inDrosophilaand have since been broadly studied in animals; however, thanks to a boom in genomic and transcriptomic data, we now know that TRP channels are present in the genomes of a variety of creatures, including green algae, fungi, choanoflagellates and a number of other eukaryotes. As a result, the organization of the TRP superfamily has changed radically from its original description. Moreover, modern comprehensive phylogenetic analyses have brought to light the vertebrate-centricity of much of the TRP literature; much of the nomenclature has been grounded in vertebrate TRP subfamilies, resulting in a glossing over of TRP channels in other taxa. Here, we provide a comprehensive review of the function, structure and evolutionary history of TRP channels, and put forth a more complete set of non-vertebrate-centric TRP family, subfamily and other subgroup nomenclature. LA - English DB - MTMT ER - TY - JOUR AU - Kuehn, Frank J. P. TI - Structure-Function Relationship of TRPM2: Recent Advances, Contradictions, and Open Questions JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 21 PY - 2020 IS - 18 PG - 16 SN - 1661-6596 DO - 10.3390/ijms21186481 UR - https://m2.mtmt.hu/api/publication/31697231 ID - 31697231 N1 - Export Date: 9 December 2020 Correspondence Address: Kühn, F.J.P.; Institute of Physiology, University Hospital RWTH AachenGermany; email: fkuehn@ukaachen.de Funding details: Deutsche Forschungsgemeinschaft, DFG, KU 2271/4-2 Funding text 1: Funding: The study was supported by the Deutsche Forschungsgemeinschaft (DFG, Grant KU 2271/4-2 to FJPK). Export Date: 7 April 2021 Correspondence Address: Kühn, F.J.P.; Institute of Physiology, Germany; email: fkuehn@ukaachen.de Chemicals/CAS: calcium, 7440-70-2, 14092-94-5; Calcium; TRPM Cation Channels; TRPM2 protein, human Funding details: Deutsche Forschungsgemeinschaft, DFG, KU 2271/4-2 Funding text 1: Funding: The study was supported by the Deutsche Forschungsgemeinschaft (DFG, Grant KU 2271/4-2 to FJPK). Export Date: 9 April 2021 Correspondence Address: Kühn, F.J.P.; Institute of Physiology, Germany; email: fkuehn@ukaachen.de Chemicals/CAS: calcium, 7440-70-2, 14092-94-5; Calcium; TRPM Cation Channels; TRPM2 protein, human Funding details: Deutsche Forschungsgemeinschaft, DFG, KU 2271/4-2 Funding text 1: Funding: The study was supported by the Deutsche Forschungsgemeinschaft (DFG, Grant KU 2271/4-2 to FJPK). Export Date: 12 April 2021 Correspondence Address: Kühn, F.J.P.; Institute of Physiology, Germany; email: fkuehn@ukaachen.de Chemicals/CAS: calcium, 7440-70-2, 14092-94-5; Calcium; TRPM Cation Channels; TRPM2 protein, human Funding details: Deutsche Forschungsgemeinschaft, DFG, KU 2271/4-2 Funding text 1: Funding: The study was supported by the Deutsche Forschungsgemeinschaft (DFG, Grant KU 2271/4-2 to FJPK). Cited By :5 Export Date: 9 September 2021 Correspondence Address: Kühn, F.J.P.; Institute of Physiology, Germany; email: fkuehn@ukaachen.de Chemicals/CAS: adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; hemagglutinin, 37333-12-3; serine, 56-45-1, 6898-95-9; calcium, 7440-70-2, 14092-94-5; Calcium; TRPM Cation Channels; TRPM2 protein, human Funding details: Deutsche Forschungsgemeinschaft, DFG, KU 2271/4-2 Funding text 1: Funding: The study was supported by the Deutsche Forschungsgemeinschaft (DFG, Grant KU 2271/4-2 to FJPK). Cited By :5 Export Date: 15 September 2021 Correspondence Address: Kühn, F.J.P.; Institute of Physiology, Germany; email: fkuehn@ukaachen.de Chemicals/CAS: adenosine triphosphate, 15237-44-2, 56-65-5, 987-65-5; hemagglutinin, 37333-12-3; serine, 56-45-1, 6898-95-9; calcium, 7440-70-2, 14092-94-5; Calcium; TRPM Cation Channels; TRPM2 protein, human Funding details: Deutsche Forschungsgemeinschaft, DFG, KU 2271/4-2 Funding text 1: Funding: The study was supported by the Deutsche Forschungsgemeinschaft (DFG, Grant KU 2271/4-2 to FJPK). AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Lu, Wei AU - Du, Juan TI - The N-terminal domain in TRPM2 channel is a conserved nucleotide binding site JF - JOURNAL OF GENERAL PHYSIOLOGY J2 - J GEN PHYSIOL VL - 152 PY - 2020 IS - 5 SN - 0022-1295 DO - 10.1085/jgp.201912555 UR - https://m2.mtmt.hu/api/publication/31366156 ID - 31366156 LA - English DB - MTMT ER - TY - JOUR AU - Zhang, H. AU - Zhao, S. AU - Yu, J. AU - Yang, W. AU - Liu, Z. AU - Zhang, L. TI - Medicinal chemistry perspective of TRPM2 channel inhibitors: where we are and where we might be heading? JF - DRUG DISCOVERY TODAY J2 - DRUG DISCOV TODAY VL - 25 PY - 2020 IS - 12 SP - 2326 EP - 2334 PG - 9 SN - 1359-6446 DO - 10.1016/j.drudis.2020.09.039 UR - https://m2.mtmt.hu/api/publication/31721987 ID - 31721987 N1 - State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China Department of Biophysics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China Export Date: 8 December 2020 CODEN: DDTOF Correspondence Address: Liu, Z.; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityChina; email: zmliu@bjmu.edu.cn Funding details: National Major Science and Technology Projects of China, 2018ZX09711001–004-005 Funding details: National Natural Science Foundation of China, NSFC, NSFC 81673279 Funding text 1: This research work was supported financially by National Natural Science Foundation of China (NSFC 81673279 ) and National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ ( 2018ZX09711001–004-005 ). We are very grateful to Tingjun Hou and Peilin Yu for reading this manuscript. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, 100191, China Department of Biophysics, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China Export Date: 9 December 2020 CODEN: DDTOF Correspondence Address: Liu, Z.; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityChina; email: zmliu@bjmu.edu.cn Funding details: National Major Science and Technology Projects of China, 2018ZX09711001–004-005 Funding details: National Natural Science Foundation of China, NSFC, NSFC 81673279 Funding text 1: This research work was supported financially by National Natural Science Foundation of China (NSFC 81673279 ) and National Science and Technology Major Projects for ‘Major New Drugs Innovation and Development’ ( 2018ZX09711001–004-005 ). We are very grateful to Tingjun Hou and Peilin Yu for reading this manuscript. AB - Transient receptor potential melastatin 2 (TRPM2) is a Ca2+- permeable nonselective cation channel that is involved in diverse biological functions as a cellular sensor for oxidative stress and temperature. It has been considered a promising therapeutic target for the treatment of ischemia/reperfusion (IR) injury, inflammation, cancer, and neurodegenerative diseases. Development of highly potent and selective TRPM2 inhibitors and validation of their use in relevant disease models will advance drug discovery. In this review, we describe the molecular structures and gating mechanism of the TRPM2 channel, and offer a comprehensive review of advances in the discovery of TRPM2 inhibitors. Furthermore, we analyze the properties of reported TRPM2 inhibitors with an emphasis on how specific inhibitors targeting this channel could be better developed. © 2020 Elsevier Ltd LA - English DB - MTMT ER -