Nomenclature: TRPM2

Family: Transient Receptor Potential channels

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

Contents

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 34,43,45,49,58
Mouse 6 1 1507 10 C1 Trpm2 transient receptor potential cation channel, subfamily M, member 2 14
Rat 6 1 1508 20p12 Trpm2 transient receptor potential cation channel, subfamily M, member 2 22
Previous and Unofficial Names
TRPC7
LTRPC2
KNP3
EREG1
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 Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Associated Proteins
Heteromeric Pore-forming Subunits
Name References
Not determined
Auxiliary Subunits
Name References
Not determined
Other Associated Proteins
Name References
ADPRibase 45,49
calmodulin 55
Sir2 13
EFHC1 28
ubiquitin 29,59
Functional Characteristics
γ = 52-60 pS at negative potentials, 76 pS at positive potentials; conducts mono- and di-valent cations non-selectively (PCa/PNa = 0.6–0.7); non-rectifying; inactivation at negative potentials; activated by oxidative stress probably via PARP-1, PARP inhibitors reduce activation by oxidative stress, activation inhibited by suppression of APDR formation by glycohydrolase inhibitors
Ion Selectivity and Conductance
Species:  Human
Rank order:  Na+ > Ca2+ > Mg2+ > Cs+ [60.0 - 80.0 pS]
References:  16,45,49,53
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. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
NAD Hs Agonist - - 3x10-4 - 1x10-3 -60.0 14,16,49,53
Conc range: 3x10-4 - 1x10-3 M [14,16,49,53]
Holding voltage: -60.0 mV
H2O2 Hs Agonist - - 5x10-7 - 5x10-5 Physiological 9,14,32,51,60
Conc range: 5x10-7 - 5x10-5 M [9,14,32,51,60]
Holding voltage: Physiological
arachidonic acid Hs Potentiation - - 1x10-5 - 3x10-5 Physiological 14
Conc range: 1x10-5 - 3x10-5 M [14]
Holding voltage: Physiological
OAADPR Hs Activation 4.0 pKd - -100.0 13
pKd 4.0 (Kd 1x10-4 M) [13]
Holding voltage: -100.0 mV
intracellular cADPR Hs Agonist 5.0 pEC50 - -80.0 – -60.0 3,30,53
pEC50 5.0 (EC50 1x10-5 M) [3,30,53]
Holding voltage: -80.0 – -60.0 mV
intracellular ADP ribose Hs Agonist 3.9 – 4.4 pEC50 - -80.0 45
pEC50 3.9 – 4.4 (EC50 3.98x10-5 – 1.26x10-4 M) [45]
Holding voltage: -80.0 mV
NAADP Hs Agonist 3.1 pEC50 - -80.0 3
pEC50 3.1 [3]
Holding voltage: -80.0 mV
intracellular Ca2+ Hs - - - - -
via calmodulin
GEA 3162 Hs - - - - -
Activator Comments
Activation of TRPM2 is regulated by [Ca2+]i. Elevated Ca2+ levels, probably via calmodulin, sensitise TRPM2 to activation by ADPR [39,55]. Heat potentiates TRPM2 activation [53]. ADP ribose, NAD, NAADP, and OAADPR might directly bind and activate TRPM2, while H2O2 and cADPR indirectly activate TRPM2 through ADP ribose [56]. Activation by oxidative stress is probably mediated by PARP-1. PARP inhibitors (SB750139>PJ34>DPQ) decrease oxidative stress-mediated activation of TRPM2 [9,65]. Catalase [19], dimethylthiourea [51] and mannitol [60] all inhibit oxidative stress-mediated TRPM2 activation.
Gating Inhibitor Comments
Glycohydrase inhibitors inhibit endogenous ADPR formation and reduce TRPM2 activation [12]. Short splice variant TRPM2-S (846 aa) inhibits activation of the long splice variant [70]. TRPM2 is inhibited by AMP (IC50=70µM), which competes with ADP ribose for Nudix domain [30,56]. Extracellular or intracellular acidosis inhibits TRPM2; the mechanism is that the extracellular protons compete with Na+ and Ca2+ for channel permeation while intracellular protons antagonize intracellular Ca2+ binding [8,52,67]. Zinc also inactivates TRPM2 and residues in the outer pore (Lys952 and Asp1002) are critical determinants of the inactivation [66].

The GY motif in the TRPM2 selective filter is essential for channel inactivation [57].
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Concentration range (M) Holding voltage (mV) Reference
flufenamic acid Hs Antagonist - - 5x10-5 - 1x10-3 -60.0 – -50.0 20,54
Conc range: 5x10-5 - 1x10-3 M [20,54]
Holding voltage: -60.0 – -50.0 mV
clotrimazole Hs Antagonist - - 3x10-6 - 3x10-5 -60.0 – -15.0 21
Conc range: 3x10-6 - 3x10-5 M [21]
Holding voltage: -60.0 – -15.0 mV
econazole Hs Antagonist - - 3x10-6 - 3x10-5 -60.0 – -15.0 21
Conc range: 3x10-6 - 3x10-5 M [21]
Holding voltage: -60.0 – -15.0 mV
miconazole Hs Antagonist - - 1x10-5 -60.0 54
Conc range: 1x10-5 M [54]
Holding voltage: -60.0 mV
2-APB Hs Antagonist 6.1 pIC50 - -60.0 54
pIC50 6.1 (IC50 8.2x10-7 M) [54]
Holding voltage: -60.0 mV
Zn2+ Hs - 6.0 pIC50 - -
pIC50 6.0 (IC50 1x10-6 M)
ACAA Hs Antagonist 5.8 pIC50 - Physiological 31
pIC50 5.8 (IC50 1.7x10-6 M) [31]
Holding voltage: Physiological
extracellular H+ Hs - - - - -
Channel Blocker Comments
Cysteine pore residues (Cys996, Cys1008) are essential for pore functions, mutations of these residues lead to dysfunctional channels [41]. Exceptionally amongst TRP channels, there is no pore block by lanthanides and heavy metal ions [32].
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:  16,40,46,53,70
Immune cells: neutrophils, monocytes, macrophages, lymphocytes (Note that TRPM2 expression in these cell types is also reported in rat and mouse).
Species:  Human
Technique:  RT-PCR, western blot, immunocytochemistry
References:  23,25,38,42,48,61,64
Pancreatic β-cells (Note that TRPM2 expression in these cells is also reported in rat and mouse).
Species:  Human
Technique:  Western blot, immunocytochemistry
References:  2,37,53
Brain/spinal cord microglia (Note that TRPM2 is also expressed in these tissues in rat).
Species:  Mouse
Technique:  In situ hybridization, RT-PCR
References:  11,15,32
Hippocampal neurons
Species:  Mouse
Technique:  In situ hybridization, western blot, immunocytochemistry
References:  44
Brain (hippocampus, cerebellum), vascular endothelium, thymocytes, pancreatic β-cells.
Species:  Mouse
Technique:  RT-PCR, western blot
References:  24,53,58,68
Dopaminergic neurons
Species:  Rat
Technique:  RT-PCR, immunohistochemistry, patch-clamp recordings, Ca2+ imaging
References:  6
Striatal neurones.
Species:  Rat
Technique:  RT-PCR
References:  22,51
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:  16,45
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging.
Species:  Mouse
Tissue:  Thymocytes.
Response measured:  Ca2+ current.
References:  24
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging.
Species:  Rat
Tissue:  Striatal neurones.
Response measured:  Ca2+ current.
References:  22,51
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging.
Species:  Mouse
Tissue:  Hippocampal neurons
Response measured:  TRPM2-mediated whole-cell current
References:  4,44
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging.
Species:  Rat
Tissue:  Microglia
Response measured:  TRPM2-mediated whole-cell current and Ca2+ elevation
References:  11,32
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging (Note that these results are also reported in mouse)
Species:  Human
Tissue:  Neutrophils
Response measured:  TRPM2-mediated Ca2+ elevation and current
References:  23,36
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging (Note that these results are also reported in mouse and rat)
Species:  Human
Tissue:  Pancreatic β-cells
Response measured:  TRPM2-mediated current and Ca2+ elevation
References:  2,37,53
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging
Species:  Human
Tissue:  B cells
Response measured:  TRPM2-mediated Ca2+ elevation
References:  48
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging
Species:  Human
Tissue:  T cells
Response measured:  TRPM2-mediated current and Ca2+ elevation
References:  3,38
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging
Species:  Mouse
Tissue:  Macrophages
Response measured:  TRPM2-mediated whole-cell current and Ca2+ elevation
References:  7,27
Patch clamp (whole-cell and single-channel recordings), Ca2+ imaging (Note that these results are also reported in mouse)
Species:  Human
Tissue:  Monocytes
Response measured:  TRPM2-mediated whole-cell current and Ca2+ elevation
References:  61,64
Patch-clamp recordings, Ca2+ imaging
Species:  Rat
Tissue:  Dopaminegic neurons
Response measured:  TRPM2-mediated whole-cell current and Ca2+ elevation
References:  6
Physiological Functions
Oxidant stress sensor, mediator of H2O2 cell death (Note that these results are also reported in mouse)
Species:  Rat
Tissue:  Insuloma cells, microglia, neurons, pancreatic β-cells
References:  10,26,35,37,40
Cytokine/ROS (reactive oxygen species) production and inflammation (Note that these results are also reported in mouse and rat)
Species:  Human
Tissue:  Monocytes, macrophages, lymphocytes
References:  7,27,42,61,64
Insulin secretion (Note that these results are also reported in mouse and rat)
Species:  Human
Tissue:  Pancreatic β-cells
References:  2,37,53
Physiological Functions Comments
Activation of TRPM2 causes predisposition to apoptosis and cell death, inhibition of TRPM2 is neuroprotective [1,12,40,71].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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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:  Nonsyndromic hereditary deafness
OMIM:  605608
Orphanet:  90636
Role: 
References:  62
Mutations not determined
Disease:  Bipolar disorder
OMIM:  125480
Role: 
References:  63,69
Mutations not determined
Disease:  Guamanian amyotrophic lateral sclerosis and parkinsonism
OMIM:  105500
Role: 
References:  17-18
Click column headers to sort
Type Species Molecular location Description Reference
Missense Human P1018L TRPM2, P1018L channels inactivate with in vitro results suggesting that the ability of TRPM2 to maintain sustained ion influx is a physiologically important function, disruption of which may contribute to disease states under certain conditions. 17
Gene Expression and Pathophysiology
Overexpression.
Tissue or cell type:  All cell types.
Pathophysiology:  Cell death, apoptosis.
Species:  None
Technique: 
References:  1,5,33,35,40,47,50

REFERENCES

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13. 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]

14. 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. Cell9 (1): 163-73. [PMID:11804595]

15. Haraguchi K, Kawamoto A, Isami K, Maeda S, Kusano A, Asakura K, Shirakawa H, Mori Y, Nakagawa T, Kaneko S. (2012) TRPM2 contributes to inflammatory and neuropathic pain through the aggravation of pronociceptive inflammatory responses in mice. J. Neurosci.32 (11): 3931-41. [PMID:22423113]

16. 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]

17. Hermosura MC, Cui AM, Go RC, Davenport B, Shetler CM, Heizer JW, Schmitz C, Mocz G, Garruto RM, Perraud AL. (2008) Altered functional properties of a TRPM2 variant in Guamanian ALS and PD. Proc. Natl. Acad. Sci. U.S.A.105 (46): 18029-34. [PMID:19004782]

18. Hermosura MC, Garruto RM. (2007) TRPM7 and TRPM2-Candidate susceptibility genes for Western Pacific ALS and PD?. Biochim. Biophys. Acta1772 (8): 822-35. [PMID:17395433]

19. 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]

20. Hill K, Benham CD, McNulty S, Randall AD. (2004) Flufenamic acid is a pH-dependent antagonist of TRPM2 channels. Neuropharmacology47 (3): 450-60. [PMID:15275834]

21. 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]

22. 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. Neuropharmacology50 (1): 89-97. [PMID:16260005]

23. Hiroi T, Wajima T, Negoro T, Ishii M, Nakano Y, Kiuchi Y, Mori Y, Shimizu S. (2013) Neutrophil TRPM2 channels are implicated in the exacerbation of myocardial ischaemia/reperfusion injury. Cardiovasc. Res.97 (2): 271-81. [PMID:23129587]

24. 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]

25. Inada H, Iida T, Tominaga M. (2006) Different expression patterns of TRP genes in murine B and T lymphocytes. Biochem. Biophys. Res. Commun.350 (3): 762-7. [PMID:17027915]

26. Kaneko S, Kawakami S, Hara Y, Wakamori M, Itoh E, Minami T, Takada Y, Kume T, Katsuki H, Mori Y et al.. (2006) A critical role of TRPM2 in neuronal cell death by hydrogen peroxide. J. Pharmacol. Sci.101 (1): 66-76. [PMID:16651700]

27. Kashio M, Sokabe T, Shintaku K, Uematsu T, Fukuta N, Kobayashi N, Mori Y, Tominaga M. (2012) Redox signal-mediated sensitization of transient receptor potential melastatin 2 (TRPM2) to temperature affects macrophage functions. Proc. Natl. Acad. Sci. U.S.A.109 (17): 6745-50. [PMID:22493272]

28. Katano M, Numata T, Aguan K, Hara Y, Kiyonaka S, Yamamoto S, Miki T, Sawamura S, Suzuki T, Yamakawa K et al.. (2012) The juvenile myoclonic epilepsy-related protein EFHC1 interacts with the redox-sensitive TRPM2 channel linked to cell death. Cell Calcium51 (2): 179-85. [PMID:22226147]

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30. 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. Cell18 (1): 61-9. [PMID:15808509]

31. 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]

32. 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]

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

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36. Lange I, Penner R, Fleig A, Beck A. (2008) Synergistic regulation of endogenous TRPM2 channels by adenine dinucleotides in primary human neutrophils. Cell Calcium44 (6): 604-15. [PMID:18572241]

37. Lange I, Yamamoto S, Partida-Sanchez S, Mori Y, Fleig A, Penner R. (2009) TRPM2 functions as a lysosomal Ca2+-release channel in beta cells. Sci Signal2 (71): ra23. [PMID:19454650]

38. Magnone M, Bauer I, Poggi A, Mannino E, Sturla L, Brini M, Zocchi E, De Flora A, Nencioni A, Bruzzone S. (2012) NAD+ levels control Ca2+ store replenishment and mitogen-induced increase of cytosolic Ca2+ by Cyclic ADP-ribose-dependent TRPM2 channel gating in human T lymphocytes. J. Biol. Chem.287 (25): 21067-81. [PMID:22547068]

39. 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]

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41. 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]

42. Melzer N, Hicking G, Göbel K, Wiendl H. (2012) TRPM2 cation channels modulate T cell effector functions and contribute to autoimmune CNS inflammation. PLoS ONE7 (10): e47617. [PMID:23077651]

43. 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. Genomics54 (1): 124-31. [PMID:9806837]

44. Olah ME, Jackson MF, Li H, Perez Y, Sun HS, Kiyonaka S, Mori Y, Tymianski M, MacDonald JF. (2009) Ca2+-dependent induction of TRPM2 currents in hippocampal neurons. J. Physiol. (Lond.)587 (Pt 5): 965-79. [PMID:19124544]

45. 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. Nature411 (6837): 595-9. [PMID:11385575]

46. Perraud AL, Schmitz C, Scharenberg AM. (2003) TRPM2 Ca2+ permeable cation channels: from gene to biological function. Cell Calcium33 (5-6): 519-31. [PMID:12765697]

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To cite this database page, please use the following:

Long-Jun Wu, David E. Clapham.
Transient Receptor Potential channels: TRPM2. Last modified on 13/02/2014. Accessed on 01/11/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=494.

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