| Structural highlights
Function
[TRPM2_HUMAN] Isoform 1: Nonselective, voltage-independent cation channel that mediates Na(+) and Ca(2+) influx, leading to increased cytoplasmic Ca(2+) levels (PubMed:11960981, PubMed:12594222, PubMed:11385575, PubMed:11509734, PubMed:11804595, PubMed:15561722, PubMed:16601673, PubMed:19171771, PubMed:20660597, PubMed:27383051, PubMed:27068538). Extracellular calcium passes through the channel and increases channel activity by binding to the cytoplasmic domain and stabilizing the channel in an open conformation (PubMed:19171771). Also contributes to Ca(2+) release from intracellular stores in response to ADP-ribose (PubMed:19454650). Plays a role in numerous processes that involve signaling via intracellular Ca(2+) levels (Probable). Besides, mediates the release of lysosomal Zn(2+) stores in response to reactive oxygen species, leading to increased cytosolic Zn(2+) levels (PubMed:25562606, PubMed:27068538). Activated by moderate heat (35 to 40 degrees Celsius) (PubMed:16601673). Activated by intracellular ADP-ribose, beta-NAD (NAD(+)) and similar compounds, and by oxidative stress caused by reactive oxygen or nitrogen species (PubMed:11960981, PubMed:11385575, PubMed:11509734, PubMed:11804595, PubMed:15561722, PubMed:16601673, PubMed:19171771, PubMed:27383051, PubMed:27068538). The precise physiological activators are under debate; the true, physiological activators may be ADP-ribose and ADP-ribose-2'-phosphate (PubMed:20650899, PubMed:25918360). Activation by ADP-ribose and beta-NAD is strongly increased by moderate heat (35 to 40 degrees Celsius) (PubMed:16601673). Likewise, reactive oxygen species lower the threshold for activation by moderate heat (37 degrees Celsius) (PubMed:22493272). Plays a role in mediating behavorial and physiological responses to moderate heat and thereby contributes to body temperature homeostasis. Plays a role in insulin secretion, a process that requires increased cytoplasmic Ca(2+) levels (By similarity). Required for normal IFNG and cytokine secretion and normal innate immune immunity in response to bacterial infection. Required for normal phagocytosis and cytokine release by macrophages exposed to zymosan (in vitro). Plays a role in dendritic cell differentiation and maturation, and in dendritic cell chemotaxis via its role in regulating cytoplasmic Ca(2+) levels (By similarity). Plays a role in the regulation of the reorganization of the actin cytoskeleton and filopodia formation in response to reactive oxygen species via its role in increasing cytoplasmic Ca(2+) and Zn(2+) levels (PubMed:27068538). Confers susceptibility to cell death following oxidative stress (PubMed:12594222, PubMed:25562606).[UniProtKB:Q91YD4][1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] Isoform 2: Lacks cation channel activity. Does not mediate cation transport in response to oxidative stress or ADP-ribose.[17] Isoform 3: Lacks cation channel activity and negatively regulates the channel activity of isoform 1. Negatively regulates susceptibility to cell death in reposponse to oxidative stress.[18]
Publication Abstract from PubMed
TRPM2 is critically involved in diverse physiological processes including core temperature sensing, apoptosis, and immune response. TRPM2's activation by Ca(2+) 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 Ca(2+) 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.
Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel.,Huang Y, Roth B, Lu W, Du J Elife. 2019 Sep 12;8. pii: 50175. doi: 10.7554/eLife.50175. PMID:31513012[19]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Perraud AL, Fleig A, Dunn CA, Bagley LA, Launay P, Schmitz C, Stokes AJ, Zhu Q, Bessman MJ, Penner R, Kinet JP, Scharenberg AM. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature. 2001 May 31;411(6837):595-9. PMID:11385575 doi:http://dx.doi.org/10.1038/35079100
- ↑ Sano Y, Inamura K, Miyake A, Mochizuki S, Yokoi H, Matsushime H, Furuichi K. Immunocyte Ca2+ influx system mediated by LTRPC2. Science. 2001 Aug 17;293(5533):1327-30. doi: 10.1126/science.1062473. PMID:11509734 doi:http://dx.doi.org/10.1126/science.1062473
- ↑ Hara Y, Wakamori M, Ishii M, Maeno E, Nishida M, Yoshida T, Yamada H, Shimizu S, Mori E, Kudoh J, Shimizu N, Kurose H, Okada Y, Imoto K, Mori Y. LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol Cell. 2002 Jan;9(1):163-73. PMID:11804595
- ↑ Wehage E, Eisfeld J, Heiner I, Jungling E, Zitt C, Luckhoff A. Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. A splice variant reveals a mode of activation independent of ADP-ribose. J Biol Chem. 2002 Jun 28;277(26):23150-6. doi: 10.1074/jbc.M112096200. Epub 2002 , Apr 17. PMID:11960981 doi:http://dx.doi.org/10.1074/jbc.M112096200
- ↑ Zhang W, Chu X, Tong Q, Cheung JY, Conrad K, Masker K, Miller BA. A novel TRPM2 isoform inhibits calcium influx and susceptibility to cell death. J Biol Chem. 2003 May 2;278(18):16222-9. doi: 10.1074/jbc.M300298200. Epub 2003, Feb 19. PMID:12594222 doi:http://dx.doi.org/10.1074/jbc.M300298200
- ↑ Perraud AL, Takanishi CL, Shen B, Kang S, Smith MK, Schmitz C, Knowles HM, Ferraris D, Li W, Zhang J, Stoddard BL, Scharenberg AM. Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels. J Biol Chem. 2005 Feb 18;280(7):6138-48. doi: 10.1074/jbc.M411446200. Epub 2004, Nov 23. PMID:15561722 doi:http://dx.doi.org/10.1074/jbc.M411446200
- ↑ Togashi K, Hara Y, Tominaga T, Higashi T, Konishi Y, Mori Y, Tominaga M. TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. EMBO J. 2006 May 3;25(9):1804-15. doi: 10.1038/sj.emboj.7601083. Epub 2006 Apr 6. PMID:16601673 doi:http://dx.doi.org/10.1038/sj.emboj.7601083
- ↑ Csanady L, Torocsik B. Four Ca2+ ions activate TRPM2 channels by binding in deep crevices near the pore but intracellularly of the gate. J Gen Physiol. 2009 Feb;133(2):189-203. doi: 10.1085/jgp.200810109. PMID:19171771 doi:http://dx.doi.org/10.1085/jgp.200810109
- ↑ Lange I, Yamamoto S, Partida-Sanchez S, Mori Y, Fleig A, Penner R. TRPM2 functions as a lysosomal Ca2+-release channel in beta cells. Sci Signal. 2009 May 19;2(71):ra23. doi: 10.1126/scisignal.2000278. PMID:19454650 doi:http://dx.doi.org/10.1126/scisignal.2000278
- ↑ Toth B, Csanady L. Identification of direct and indirect effectors of the transient receptor potential melastatin 2 (TRPM2) cation channel. J Biol Chem. 2010 Sep 24;285(39):30091-102. doi: 10.1074/jbc.M109.066464. Epub, 2010 Jul 22. PMID:20650899 doi:http://dx.doi.org/10.1074/jbc.M109.066464
- ↑ Yang W, Zou J, Xia R, Vaal ML, Seymour VA, Luo J, Beech DJ, Jiang LH. State-dependent inhibition of TRPM2 channel by acidic pH. J Biol Chem. 2010 Oct 1;285(40):30411-8. doi: 10.1074/jbc.M110.139774. Epub 2010 , Jul 26. PMID:20660597 doi:http://dx.doi.org/10.1074/jbc.M110.139774
- ↑ Kashio M, Sokabe T, Shintaku K, Uematsu T, Fukuta N, Kobayashi N, Mori Y, Tominaga M. Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6745-50. doi:, 10.1073/pnas.1114193109. Epub 2012 Apr 9. PMID:22493272 doi:http://dx.doi.org/10.1073/pnas.1114193109
- ↑ Manna PT, Munsey TS, Abuarab N, Li F, Asipu A, Howell G, Sedo A, Yang W, Naylor J, Beech DJ, Jiang LH, Sivaprasadarao A. TRPM2-mediated intracellular Zn2+ release triggers pancreatic beta-cell death. Biochem J. 2015 Mar 15;466(3):537-46. doi: 10.1042/BJ20140747. PMID:25562606 doi:http://dx.doi.org/10.1042/BJ20140747
- ↑ Toth B, Iordanov I, Csanady L. Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist ADP-ribose-2'-phosphate. J Gen Physiol. 2015 May;145(5):419-30. doi: 10.1085/jgp.201511377. PMID:25918360 doi:http://dx.doi.org/10.1085/jgp.201511377
- ↑ Li F, Abuarab N, Sivaprasadarao A. Reciprocal regulation of actin cytoskeleton remodelling and cell migration by Ca2+ and Zn2+: role of TRPM2 channels. J Cell Sci. 2016 May 15;129(10):2016-29. doi: 10.1242/jcs.179796. Epub 2016 Apr, 11. PMID:27068538 doi:http://dx.doi.org/10.1242/jcs.179796
- ↑ Iordanov I, Mihalyi C, Toth B, Csanady L. The proposed channel-enzyme transient receptor potential melastatin 2 does not possess ADP ribose hydrolase activity. Elife. 2016 Jul 6;5. doi: 10.7554/eLife.17600. PMID:27383051 doi:http://dx.doi.org/10.7554/eLife.17600
- ↑ Wehage E, Eisfeld J, Heiner I, Jungling E, Zitt C, Luckhoff A. Activation of the cation channel long transient receptor potential channel 2 (LTRPC2) by hydrogen peroxide. A splice variant reveals a mode of activation independent of ADP-ribose. J Biol Chem. 2002 Jun 28;277(26):23150-6. doi: 10.1074/jbc.M112096200. Epub 2002 , Apr 17. PMID:11960981 doi:http://dx.doi.org/10.1074/jbc.M112096200
- ↑ Zhang W, Chu X, Tong Q, Cheung JY, Conrad K, Masker K, Miller BA. A novel TRPM2 isoform inhibits calcium influx and susceptibility to cell death. J Biol Chem. 2003 May 2;278(18):16222-9. doi: 10.1074/jbc.M300298200. Epub 2003, Feb 19. PMID:12594222 doi:http://dx.doi.org/10.1074/jbc.M300298200
- ↑ Huang Y, Roth B, Lu W, Du J. Ligand recognition and gating mechanism through three ligand-binding sites of human TRPM2 channel. Elife. 2019 Sep 12;8. pii: 50175. doi: 10.7554/eLife.50175. PMID:31513012 doi:http://dx.doi.org/10.7554/eLife.50175
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