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TRPM2

Family: Transient Receptor Potential channels

Contents:
Gene and Protein Information
Previous and Unofficial Names
Database Links
Associated Proteins
Ion Selectivity and Conductance
Voltage Dependence
Activators
Gating Inhibitors
Pore Blockers
Tissue Distribution
Functional Assays
Physiological Functions
Phenotypes, Alleles and Disease Models
Clinically-Relevant Mutations and Pathophysiology
Gene Expression and Pathophysiology
References
Gene and Protein Information
Species TM P Loops AA Chromosomal Location Gene Symbol Gene Name Reference
Human 6 1 1503 21q22.3 TRPM2 transient receptor potential cation channel, subfamily M, member 2 18,23-24,27,33
Mouse 6 1 1507 10 C1 Trpm2 transient receptor potential cation channel, subfamily M, member 2 7
Rat 6 1 1508 20p12 Trpm2 transient receptor potential cation channel, subfamily M, member 2 12
Previous and Unofficial Names
TRPC7
LTRPC2
KNP3
EREG1
NUDT9L1
NUDT9H
LOC294329
Trpm2-predicted
null
transient receptor potential cation channel subfamily M member 2
transient receptor potential cation channel, subfamily M, member 2
transient receptor potential cation channel, subfamily M, member 2 (predicted)
transient receptor potential melastatin family 2
Trrp7
9830168K16Rik
C79133
Database Links
Ensembl ENSG00000142185 (Hs), ENSMUSG00000009292 (Mm), ENSRNOG00000001216 (Rn)
Entrez Gene 7226 (Hs), 28240 (Mm), 294329 (Rn)
GeneCards TRPM2 (Hs)
GenitoUrinary Development Molecular Anatomy Project Trpm2 (Mm)
HomoloGene 20709 (Hs)
Human Protein Reference Database 04777 (Hs)
InterPro O94759 (Hs), Q91YD4 (Mm)
KEGG Gene hsa:7226 (Hs), mmu:28240 (Mm), rno:294329 (Rn)
OMIM 603749 (Hs)
PharmGKB Gene PA37012 (Hs)
PhosphoSitePlus O94759 (Hs), Q91YD4 (Mm)
Protein Ontology (PRO) PRO:000016698 (Hs)
RefSeq Nucleotide NM_003307 (Hs), NM_138301 (Mm), NM_001011559 (Rn)
RefSeq Protein NP_003298 (Hs), NP_612174 (Mm), NP_001011559 (Rn)
TreeFam ENSG00000142185 (Hs), ENSMUSG00000009292 (Mm), ENSRNOG00000001216 (Rn)
UniGene Hs. 369759 (Hs)
UniProt O94759 (Hs), Q91YD4 (Mm)
Wikipedia TRPM2
Transient Receptor Potential channels
Search for 3D structures on the PDB
Search by keyword: Transient Receptor Potential channels TRPM2 Search by accession number: O94759, Q91YD4
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
ADPRibase 24,27
calmodulin 32
Sir2 6
Ion Selectivity and Conductance
Species:  Human
Rank order:  Na+ > Ca2+ > Mg2+ > Cs+ [60.0 - 80.0 pS]
References:  8,24,27,30
Ion Selectivity and Conductance Comments
Ranking shown is for 20°C. At >35°C, PCa:PNa ≈ 6.
Voltage Dependence Comments
Voltage independent.
Other chemical activators (Human)
agents producing reactive oxygen (e.g. H2O2) and nitrogen (e.g. GEA 3162) species
Physical activators (Human)
heat ~ 35°C
Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
NAD Hs - - 3x10-4 - 1x10-3 -60.0 7-8,27,30
H2O2 Hs - - 5x10-7 - 5x10-5 Physiological 4,7,16,29,34
arachidonic acid Hs - - 1x10-5 - 3x10-5 Physiological 7
cADPR Hs 5.0 pEC50 - -80.0 – -60.0 2,14,30
ADP ribose Hs 3.9 – 4.4 pEC50 - -80.0 24
NAADP Hs 3.1 pEC50 - -80.0 2
Activator Comments
Activation of TRPM2 is regulated by [Ca2+]i. Elevated Ca2+ levels, probably via calmodulin, sensitise TRPM2 to activation by ADPR [20,32]. Heat potentiates TRPM2 activation [30]. Activation by oxidative stress is probably mediated by PARP-1. PARP inhibitors (SB750139>PJ34>DPQ) decrease oxidative stress-mediated activation of TRPM2 [4,37]. Catalase [9], dimethylthiourea [29] and mannitol [34] all inhibit oxidative stress-mediated TRPM2 activation.
Gating Inhibitor Comments
Glycohydrase inhibitors inhibit endogenous ADPR formation and reduce TRPM2 activation [5]. Short splice variant TRPM2-S (846 aa) inhibits activation of the long splice variant [40].
Pore Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Affinity Units Concentration range (M) Holding voltage (mV) Reference
flufenamic acid Hs - - 5x10-5 - 1x10-3 -60.0 – -50.0 10,31
clotrimazole Hs - - 3x10-6 - 3x10-5 -60.0 – -15.0 11
econazole Hs - - 3x10-6 - 3x10-5 -60.0 – -15.0 11
miconazole Hs - - 1x10-5 -60.0 31
2-APB Hs 6.1 pIC50 - -60.0 31
ACAA Hs 5.8 pIC50 - Physiological 15
Pore Blocker Comments
Cysteine pore residues (Cys996, Cys1008) are essential for pore functions, mutations of these residues lead to dysfunctional channels [22]. Exceptionally amongst TRP channels, there is no pore block by lanthanides and heavy metal ions [16].
Tissue Distribution
Brain (cerebellum, cortex, medulla, temporal lobe, occipital lobe, frontal lobe, putamen, caudate, amygdala, hippocampus, striatum), spinal cord, bone marrow, spleen, heart, lung, eye, neutrophils, leukocytes, pancreatic β-cells.
Species:  Human
Technique:  RT-PCR, Western Blot, Northern Blot, Immunocytochemistry
References:  8,21,25,30,40
Brain (hippocampus, cerebellum), vascular endothelium, thymocytes, pancreatic β-cells.
Species:  Mouse
Technique:  RT-PCR, Western Blotting.
References:  13,30,33,38
Striatal neurones.
Species:  Rat
Technique:  RT-PCR
References:  12,29
Functional Assays
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging.
Species:  Human
Tissue:  HEK 293 cells, neutrophil granulocytes.
Response measured:  Ca2+ current.
References:  8,24
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging.
Species:  Mouse
Tissue:  Thymocytes.
Response measured:  Ca2+ current.
References:  13
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging.
Species:  Rat
Tissue:  Striatal neurones.
Response measured:  Ca2+ current.
References:  12,29
Physiological Functions
Oxidant stress sensor, mediator of H2O2 cell death.
Species:  Rat
Tissue:  Insuloma cells, microglia.
References:  19,21
Physiological Functions Comments
Activation of TRPM2 causes predisposition to apoptosis and cell death, inhibition of TRPM2 is neuroprotective [1,5,21,41].
Phenotypes, Alleles and Disease Models Mouse data from MGI

Click here to show/hide data

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Trpm2tm1Yamo Trpm2tm1Yamo/Trpm2tm1Yamo
involves: 129S4/SvJae * C57BL/6J		 MGI:1351901  MP:0008750 abnormal interferon level PMID: 18542050 
Trpm2tm1Yamo Trpm2tm1Yamo/Trpm2tm1Yamo
involves: 129S4/SvJae * C57BL/6J		 MGI:1351901  MP:0008751 abnormal interleukin level PMID: 18542050 
Trpm2tm1Yamo Trpm2tm1Yamo/Trpm2tm1Yamo
involves: 129S4/SvJae * C57BL/6J		 MGI:1351901  MP:0002442 abnormal leukocyte physiology PMID: 18542050 
Trpm2tm1Yamo Trpm2tm1Yamo/Trpm2tm1Yamo
involves: 129S4/SvJae * C57BL/6J		 MGI:1351901  MP:0002451 abnormal macrophage physiology PMID: 18542050 
Trpm2tm1Yamo Trpm2tm1Yamo/Trpm2tm1Yamo
involves: 129S4/SvJae * C57BL/6J		 MGI:1351901  MP:0001876 decreased inflammatory response PMID: 18542050 
Trpm2tm1Yamo Trpm2tm1Yamo/Trpm2tm1Yamo
involves: 129S4/SvJae * C57BL/6J		 MGI:1351901  MP:0008719 impaired neutrophil recruitment PMID: 18542050 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Bipolar disorder.
OMIM:  125480
Role:  Downregulation or mutation of TRPM2 may be associated with bipolar disorder.
References:  36,39
Mutations not determined
Disease:  Nonsyndromic hereditary deafness
OMIM:  605608
Orphanet:  90636
Role:  Downregulation or mutation of TRPM2 may be associated with nonsyndromic hereditary deafness.
References:  35
Mutations not determined
Gene Expression and Pathophysiology
Overexpression.
Tissue or cell type:  All cell types.
Pathophysiology:  Cell death, apoptosis.
Species:  None
Technique: 
References:  1,3,17,19,21,26,28

REFERENCES

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1. Aarts, MM; Tymianski, M. (2005) TRPMs and neuronal cell death. Pflugers Arch., 451 (1): 243-9. [PMID:16044308]

2. Beck, A; Kolisek, M; Bagley, LA; Fleig, A; Penner, R. (2006) Nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose regulate TRPM2 channels in T lymphocytes. FASEB J., 20 (7): 962-4. [PMID:16585058]

3. Chubanov, V; Gudermann, T; Schlingmann, KP. (2005) Essential role for TRPM6 in epithelial magnesium transport and body magnesium homeostasis. Pflugers Arch., 451 (1): 228-34. [PMID:16075242]

4. Fonfria, E; Marshall, IC; Benham, CD; Boyfield, I; Brown, JD; Hill, K; Hughes, JP; Skaper, SD; McNulty, S. (2004) TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Br. J. Pharmacol., 143 (1): 186-92. [PMID:15302683]

5. Gasser, A; Glassmeier, G; Fliegert, R; Langhorst, MF; Meinke, S; Hein, D; Kruger, S; Weber, K; Heiner, I; Oppenheimer, N; Schwarz, JR; Guse, AH. (2006) Activation of T cell calcium influx by the second messenger ADP-ribose. J. Biol. Chem., 281 (5): 2489-96. [PMID:16316998]

6. Grubisha, O; Rafty, LA; Takanishi, CL; Xu, X; Tong, L; Perraud, AL; Scharenberg, AM; Denu, JM. (2006) Metabolite of SIR2 reaction modulates TRPM2 ion channel. J. Biol. Chem., 281 (20): 14057-65. [PMID:16565078]

7. 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. (2002) LTRPC2 Ca2+-permeable channel activated by changes in redox status confers susceptibility to cell death. Mol. Cell, 9 (1): 163-73. [PMID:11804595]

8. Heiner, I; Eisfeld, J; Halaszovich, CR; Wehage, E; Jungling, E; Zitt, C; Luckhoff, A. (2003) Expression profile of the transient receptor potential (TRP) family in neutrophil granulocytes: evidence for currents through long TRP channel 2 induced by ADP-ribose and NAD. Biochem. J., 371 (Pt 3): 1045-53. [PMID:12564954]

9. Herson, PS; Dulock, KA; Ashford, ML. (1997) Characterization of a nicotinamide-adenine dinucleotide-dependent cation channel in the CRI-G1 rat insulinoma cell line. J. Physiol. (Lond.), 505 ( Pt 1): 65-76. [PMID:9409472]

10. Hill, K; Benham, CD; McNulty, S; Randall, AD. (2004) Flufenamic acid is a pH-dependent antagonist of TRPM2 channels. Neuropharmacology, 47 (3): 450-60. [PMID:15275834]

11. Hill, K; McNulty, S; Randall, AD. (2004) Inhibition of TRPM2 channels by the antifungal agents clotrimazole and econazole. Naunyn Schmiedebergs Arch. Pharmacol., 370 (4): 227-37. [PMID:15549272]

12. Hill, K; Tigue, NJ; Kelsell, RE; Benham, CD; McNulty, S; Schaefer, M; Randall, AD. (2006) Characterisation of recombinant rat TRPM2 and a TRPM2-like conductance in cultured rat striatal neurones. Neuropharmacology, 50 (1): 89-97. [PMID:16260005]

13. Hurne, AM; Chai, CL; Moerman, K; Waring, P. (2002) Influx of calcium through a redox-sensitive plasma membrane channel in thymocytes causes early necrotic cell death induced by the epipolythiodioxopiperazine toxins. J. Biol. Chem., 277 (35): 31631-8. [PMID:12063251]

14. Kolisek, M; Beck, A; Fleig, A; Penner, R. (2005) Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels. Mol. Cell, 18 (1): 61-9. [PMID:15808509]

15. Kraft, R; Grimm, C; Frenzel, H; Harteneck, C. (2006) Inhibition of TRPM2 cation channels by N-(p-amylcinnamoyl)anthranilic acid. Br. J. Pharmacol., 148 (3): 264-73. [PMID:16604090]

16. Kraft, R; Grimm, C; Grosse, K; Hoffmann, A; Sauerbruch, S; Kettenmann, H; Schultz, G; Harteneck, C. (2004) Hydrogen peroxide and ADP-ribose induce TRPM2-mediated calcium influx and cation currents in microglia. Am. J. Physiol., Cell Physiol., 286 (1): C129-37. [PMID:14512294]

17. Kraft, R; Harteneck, C. (2005) The mammalian melastatin-related transient receptor potential cation channels: an overview. Pflugers Arch., 451 (1): 204-11. [PMID:15895246]

18. Kudoh, J; Nagamine, K; Asakawa, S; Abe, I; Kawasaki, K; Maeda, H; Tsujimoto, S; Minoshima, S; Ito, F; Shimizu, N. (1997) Localization of 16 exons to a 450-kb region involved in the autoimmune polyglandular disease type I (APECED) on human chromosome 21q22.3. DNA Res., 4 (1): 45-52. [PMID:9179495]

19. Kuhn, FJ; Heiner, I; Luckhoff, A. (2005) TRPM2: a calcium influx pathway regulated by oxidative stress and the novel second messenger ADP-ribose. Pflugers Arch., 451 (1): 212-9. [PMID:15952035]

20. McHugh, D; Flemming, R; Xu, SZ; Perraud, AL; Beech, DJ. (2003) Critical intracellular Ca2+ dependence of transient receptor potential melastatin 2 (TRPM2) cation channel activation. J. Biol. Chem., 278 (13): 11002-6. [PMID:12529379]

21. McNulty, S; Fonfria, E. (2005) The role of TRPM channels in cell death. Pflugers Arch., 451 (1): 235-42. [PMID:16025303]

22. Mei, ZZ; Mao, HJ; Jiang, LH. (2006) Conserved cysteine residues in the pore region are obligatory for human TRPM2 channel function. Am. J. Physiol., Cell Physiol., 291 (5): C1022-8. [PMID:16822940]

23. Nagamine, K; Kudoh, J; Minoshima, S; Kawasaki, K; Asakawa, S; Ito, F; Shimizu, N. (1998) Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. Genomics, 54 (1): 124-31. [PMID:9806837]

24. Perraud, AL; Fleig, A; Dunn, CA; Bagley, LA; Launay, P; Schmitz, C; Stokes, AJ; Zhu, Q; Bessman, MJ; Penner, R; Kinet, JP; Scharenberg, AM. (2001) ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature, 411 (6837): 595-9. [PMID:11385575]

25. Perraud, AL; Schmitz, C; Scharenberg, AM. (2003) TRPM2 Ca2+ permeable cation channels: from gene to biological function. Cell Calcium, 33 (5-6): 519-31. [PMID:12765697]

26. Reid, G. (2005) ThermoTRP channels and cold sensing: what are they really up to?. Pflugers Arch., 451 (1): 250-63. [PMID:16075243]

27. Sano, Y; Inamura, K; Miyake, A; Mochizuki, S; Yokoi, H; Matsushime, H; Furuichi, K. (2001) Immunocyte Ca2+ influx system mediated by LTRPC2. Science, 293 (5533): 1327-30. [PMID:11509734]

28. Scharenberg, AM. (2005) TRPM2 and TRPM7: channel/enzyme fusions to generate novel intracellular sensors. Pflugers Arch., 451 (1): 220-7. [PMID:16001276]

29. Smith, MA; Herson, PS; Lee, K; Pinnock, RD; Ashford, ML. (2003) Hydrogen-peroxide-induced toxicity of rat striatal neurones involves activation of a non-selective cation channel. J. Physiol. (Lond.), 547 (Pt 2): 417-25. [PMID:12562896]

30. Togashi, K; Hara, Y; Tominaga, T; Higashi, T; Konishi, Y; Mori, Y; Tominaga, M. (2006) TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. EMBO J., 25 (9): 1804-15. [PMID:16601673]

31. Togashi, K; Inada, H; Tominaga, M. (2008) Inhibition of the transient receptor potential cation channel TRPM2 by 2-aminoethoxydiphenyl borate (2-APB). Br. J. Pharmacol., 153 (6): 1324-30. [PMID:18204483]

32. Tong, Q; Zhang, W; Conrad, K; Mostoller, K; Cheung, JY; Peterson, BZ; Miller, BA. (2006) Regulation of the transient receptor potential channel TRPM2 by the Ca2+ sensor calmodulin. J. Biol. Chem., 281 (14): 9076-85. [PMID:16461353]

33. Uemura, T; Kudoh, J; Noda, S; Kanba, S; Shimizu, N. (2005) Characterization of human and mouse TRPM2 genes: identification of a novel N-terminal truncated protein specifically expressed in human striatum. Biochem. Biophys. Res. Commun., 328 (4): 1232-43. [PMID:15708008]

34. Wehage, E; Eisfeld, J; Heiner, I; Jungling, E; Zitt, C; Luckhoff, A. (2002) 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., 277 (26): 23150-6. [PMID:11960981]

35. Wilcox, ER; Burton, QL; Naz, S; Riazuddin, S; Smith, TN; Ploplis, B; Belyantseva, I; Ben-Yosef, T; Liburd, NA; Morell, RJ; Kachar, B; Wu, DK; Griffith, AJ; Riazuddin, S; Friedman, TB. (2001) Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell, 104 (1): 165-72. [PMID:11163249]

36. Xu, C; Macciardi, F; Li, PP; Yoon, IS; Cooke, RG; Hughes, B; Parikh, SV; McIntyre, RS; Kennedy, JL; Warsh, JJ. (2006) Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder. Am. J. Med. Genet. B Neuropsychiatr. Genet., 141B (1): 36-43. [PMID:16252251]

37. Yang, KT; Chang, WL; Yang, PC; Chien, CL; Lai, MS; Su, MJ; Wu, ML. (2006) Activation of the transient receptor potential M2 channel and poly(ADP-ribose) polymerase is involved in oxidative stress-induced cardiomyocyte death. Cell Death Differ., 13 (10): 1815-26. [PMID:16294211]

38. Yao, X; Garland, CJ. (2005) Recent developments in vascular endothelial cell transient receptor potential channels. Circ. Res., 97 (9): 853-63. [PMID:16254217]

39. Yoon, IS; Li, PP; Siu, KP; Kennedy, JL; Macciardi, F; Cooke, RG; Parikh, SV; Warsh, JJ. (2001) Altered TRPC7 gene expression in bipolar-I disorder. Biol. Psychiatry, 50 (8): 620-6. [PMID:11690598]

40. Zhang, W; Chu, X; Tong, Q; Cheung, JY; Conrad, K; Masker, K; Miller, BA. (2003) A novel TRPM2 isoform inhibits calcium influx and susceptibility to cell death. J. Biol. Chem., 278 (18): 16222-9. [PMID:12594222]

41. Zhang, W; Hirschler-Laszkiewicz, I; Tong, Q; Conrad, K; Sun, SC; Penn, L; Barber, DL; Stahl, R; Carey, DJ; Cheung, JY; Miller, BA. (2006) TRPM2 is an ion channel that modulates hematopoietic cell death through activation of caspases and PARP cleavage. Am. J. Physiol., Cell Physiol., 290 (4): C1146-59. [PMID:16306129]

To cite this database page, please use the following:

David E. Clapham, Bernd Nilius, Grzegorz Owsianik.
Transient Receptor Potential channels: TRPM2. Last modified on 01/03/2012. Accessed on 21/05/2013. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=494.


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