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Gene Review

TRPM2  -  transient receptor potential cation...

Homo sapiens

Synonyms: EREG1, Estrogen-responsive element-associated gene 1 protein, KNP3, LTRPC2, LTrpC-2, ...
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Disease relevance of TRPM2

  • This novel TRPC7 gene could be a candidate gene for genetic disorders such as bipolar affective disorder, nonsyndromic hereditary deafness, Knobloch syndrome, and holoprosencephaly, which were mapped to this region [1].
  • These data provide a functional characterisation of heterologously expressed rTRPM2 and demonstrate that, in addition to the previous descriptions in immune cells, microglia and insulinomas, a TRPM2-like conductance can be found in neurones derived from the rodent CNS [2].
  • Activation of TRPM2 in microglia during ischemic brain injury may mediate key aspects of microglial pathophysiological responses [3].
  • The highest homologies are observed with the human TRPC7 and with melastatin 1 ( MLSN1 ), whose transcript is downregulated in metastatic melanomas [4].

Psychiatry related information on TRPM2


High impact information on TRPM2

  • ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology [6].
  • The expression of native LTRPC2 transcripts is detectable in many tissues including the U937 monocyte cell line, in which ADPR induces large cation currents (designated IADPR) that closely match those mediated by recombinant LTRPC2 [6].
  • Intracellular pyrimidine nucleotides, adenosine 5'-diphosphoribose (ADPR), and nicotinamide adenine dinucleotide (NAD), directly activated LTRPC2, which functioned as a Ca2+-permeable nonselective cation channel and enabled Ca2+ influx into cells [7].
  • The melastatin-related transient receptor potential channel TRPM2 is a plasma membrane Ca2+-permeable cation channel that is activated by intracellular adenosine diphosphoribose (ADPR) binding to the channel's enzymatic Nudix domain [8].
  • Our results establish TRPM2 as a coincidence detector for ADPR and cADPR signaling and provide a functional context for cADPR as a second messenger for Ca2+ influx [8].

Chemical compound and disease context of TRPM2

  • 5. SB750139-B, PJ34 and DPQ inhibited increases in [Ca(2+)](i) in a rat insulinoma cell line (CRI-G1 cells) endogenously expressing TRPM2 (pIC(50) vs 100 microm H(2)O(2): 7.64+/-0.38; 6.68+/-0.28; 4.78+/-0.05, respectively) [9].
  • Pharmacologically, rTRPM2 is rapidly and irreversibly blocked by clotrimazole (10muM), thus resembling hTRPM2 but not the TRPM2-like current of the rat-derived insulinoma CRI-G1, which exhibits reversible inhibition by this agent [2].
  • Response to ADP-ribose by activation of TRPM2 in the CRI-G1 insulinoma cell line [10].

Biological context of TRPM2

  • Here we show through structure-guided mutagenesis that TRPM2 gating by ADP-ribose and both oxidative and nitrosative stresses requires an intact ADP-ribose binding cleft in the C-terminal nudix domain [11].
  • Electrophysiological recordings demonstrated the presence of functional TRPM7, a constitutively active cation channel sensitive to intracellular Mg(2+), and TRPM2, an ADP-ribose-dependent cation channel activated by oxidative stress [12].
  • Thus, stimulation of TRPM2 is likely to occur after activation of CD38 (producing ADP-ribose) and during the oxidative burst (enhancing the NAD concentration) [13].
  • 2. Using patch-clamp and calcium-imaging techniques, we show that extracellular application of 20 microM ACA completely blocked ADPR-induced whole-cell currents and H2O2-induced Ca2+ signals (IC50 = 1.7 microM) in HEK293 cells transfected with human TRPM2 [14].
  • We tested this hypothesis by examining the association of selected single nucleotide polymorphisms (SNPs) and their haplotypes, spanning the TRPM2 gene, with BD and BLCL [Ca(2+)](B), in a case control design [15].

Anatomical context of TRPM2


Associations of TRPM2 with chemical compounds


Regulatory relationships of TRPM2


Other interactions of TRPM2

  • NUDT9 shares 39% sequence identity with the C-terminal cytoplasmic domain of the ADPR-gated calcium channel TRPM2, which exhibits low but specific enzyme activity [22].
  • 6 2-APB also blocks TRPC6 and TRPM3 expressed in HEK-293 cells, but not TRPM2 [23].
  • Mammalian transient receptor potential channels (TRPCs) form a family of Ca(2+)-permeable cation channels currently consisting of seven members, TRPC1-TRPC7 [24].
  • We found that 2APB partially inhibits divalent cation entry in cells expressing TRPC3, TRPC6, or TRPC7 and that this partial inhibition was observed whether the channels were activated by a muscarinic agonist or by OAG [25].
  • To date, two TRPM family members, TRPM2 and TRPM7, have been implicated directly as central components of cell death pathways [26].

Analytical, diagnostic and therapeutic context of TRPM2


  1. Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain. Nagamine, K., Kudoh, J., Minoshima, S., Kawasaki, K., Asakawa, S., Ito, F., Shimizu, N. Genomics (1998) [Pubmed]
  2. Characterisation of recombinant rat TRPM2 and a TRPM2-like conductance in cultured rat striatal neurones. Hill, K., Tigue, N.J., Kelsell, R.E., Benham, C.D., McNulty, S., Schaefer, M., Randall, A.D. Neuropharmacology (2006) [Pubmed]
  3. TRPM2 is elevated in the tMCAO stroke model, transcriptionally regulated, and functionally expressed in C13 microglia. Fonfria, E., Mattei, C., Hill, K., Brown, J.T., Randall, A., Benham, C.D., Skaper, S.D., Campbell, C.A., Crook, B., Murdock, P.R., Wilson, J.M., Maurio, F.P., Owen, D.E., Tilling, P.L., McNulty, S. J. Recept. Signal Transduct. Res. (2006) [Pubmed]
  4. Identification and characterization of MTR1, a novel gene with homology to melastatin (MLSN1) and the trp gene family located in the BWS-WT2 critical region on chromosome 11p15.5 and showing allele-specific expression. Prawitt, D., Enklaar, T., Klemm, G., Gärtner, B., Spangenberg, C., Winterpacht, A., Higgins, M., Pelletier, J., Zabel, B. Hum. Mol. Genet. (2000) [Pubmed]
  5. Characterization of human and mouse TRPM2 genes: identification of a novel N-terminal truncated protein specifically expressed in human striatum. Uemura, T., Kudoh, J., Noda, S., Kanba, S., Shimizu, N. Biochem. Biophys. Res. Commun. (2005) [Pubmed]
  6. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Perraud, A.L., Fleig, A., Dunn, C.A., Bagley, L.A., Launay, P., Schmitz, C., Stokes, A.J., Zhu, Q., Bessman, M.J., Penner, R., Kinet, J.P., Scharenberg, A.M. Nature (2001) [Pubmed]
  7. Immunocyte Ca2+ influx system mediated by LTRPC2. Sano, Y., Inamura, K., Miyake, A., Mochizuki, S., Yokoi, H., Matsushime, H., Furuichi, K. Science (2001) [Pubmed]
  8. Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels. Kolisek, M., Beck, A., Fleig, A., Penner, R. Mol. Cell (2005) [Pubmed]
  9. TRPM2 channel opening in response to oxidative stress is dependent on activation of poly(ADP-ribose) polymerase. Fonfria, E., Marshall, I.C., Benham, C.D., Boyfield, I., Brown, J.D., Hill, K., Hughes, J.P., Skaper, S.D., McNulty, S. Br. J. Pharmacol. (2004) [Pubmed]
  10. Response to ADP-ribose by activation of TRPM2 in the CRI-G1 insulinoma cell line. Inamura, K., Sano, Y., Mochizuki, S., Yokoi, H., Miyake, A., Nozawa, K., Kitada, C., Matsushime, H., Furuichi, K. J. Membr. Biol. (2003) [Pubmed]
  11. Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels. Perraud, A.L., Takanishi, C.L., Shen, B., Kang, S., Smith, M.K., Schmitz, C., Knowles, H.M., Ferraris, D., Li, W., Zhang, J., Stoddard, B.L., Scharenberg, A.M. J. Biol. Chem. (2005) [Pubmed]
  12. Molecular and electrophysiological characterization of transient receptor potential ion channels in the primary murine megakaryocyte. Carter, R.N., Tolhurst, G., Walmsley, G., Vizuete-Forster, M., Miller, N., Mahaut-Smith, M.P. J. Physiol. (Lond.) (2006) [Pubmed]
  13. Role and regulation of TRP channels in neutrophil granulocytes. Heiner, I., Eisfeld, J., Lückhoff, A. Cell Calcium (2003) [Pubmed]
  14. Inhibition of TRPM2 cation channels by N-(p-amylcinnamoyl)anthranilic acid. Kraft, R., Grimm, C., Frenzel, H., Harteneck, C. Br. J. Pharmacol. (2006) [Pubmed]
  15. Association of the putative susceptibility gene, transient receptor potential protein melastatin type 2, with bipolar disorder. Xu, C., Macciardi, F., Li, P.P., Yoon, I.S., Cooke, R.G., Hughes, B., Parikh, S.V., McIntyre, R.S., Kennedy, J.L., Warsh, J.J. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2006) [Pubmed]
  16. Activation of T cell calcium influx by the second messenger ADP-ribose. Gasser, A., Glassmeier, G., Fliegert, R., Langhorst, M.F., Meinke, S., Hein, D., Krüger, S., Weber, K., Heiner, I., Oppenheimer, N., Schwarz, J.R., Guse, A.H. J. Biol. Chem. (2006) [Pubmed]
  17. Critical intracellular Ca2+ dependence of transient receptor potential melastatin 2 (TRPM2) cation channel activation. McHugh, D., Flemming, R., Xu, S.Z., Perraud, A.L., Beech, D.J. J. Biol. Chem. (2003) [Pubmed]
  18. Conserved cysteine residues in the pore region are obligatory for human TRPM2 channel function. Mei, Z.Z., Mao, H.J., Jiang, L.H. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  19. The transmembrane segment S6 determines cation versus anion selectivity of TRPM2 and TRPM8. Kühn, F.J., Knop, G., Lückhoff, A. J. Biol. Chem. (2007) [Pubmed]
  20. TRPM2 is an ion channel that modulates hematopoietic cell death through activation of caspases and PARP cleavage. Zhang, W., Hirschler-Laszkiewicz, I., Tong, Q., Conrad, K., Sun, S.C., Penn, L., Barber, D.L., Stahl, R., Carey, D.J., Cheung, J.Y., Miller, B.A. Am. J. Physiol., Cell Physiol. (2006) [Pubmed]
  21. Transient receptor potential (TRP) protein 7 acts as a G protein-activated Ca(2+) channel mediating angiotensin II-induced myocardial apoptosis. Satoh, S., Tanaka, H., Ueda, Y., Oyama, J., Sugano, M., Sumimoto, H., Mori, Y., Makino, N. Mol. Cell. Biochem. (2007) [Pubmed]
  22. The crystal structure and mutational analysis of human NUDT9. Shen, B.W., Perraud, A.L., Scharenberg, A., Stoddard, B.L. J. Mol. Biol. (2003) [Pubmed]
  23. Block of TRPC5 channels by 2-aminoethoxydiphenyl borate: a differential, extracellular and voltage-dependent effect. Xu, S.Z., Zeng, F., Boulay, G., Grimm, C., Harteneck, C., Beech, D.J. Br. J. Pharmacol. (2005) [Pubmed]
  24. Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5. Schaefer, M., Plant, T.D., Obukhov, A.G., Hofmann, T., Gudermann, T., Schultz, G. J. Biol. Chem. (2000) [Pubmed]
  25. Mechanism of inhibition of TRPC cation channels by 2-aminoethoxydiphenylborane. Lievremont, J.P., Bird, G.S., Putney, J.W. Mol. Pharmacol. (2005) [Pubmed]
  26. The role of TRPM channels in cell death. McNulty, S., Fonfria, E. Pflugers Arch. (2005) [Pubmed]
  27. TRPM2: a calcium influx pathway regulated by oxidative stress and the novel second messenger ADP-ribose. Kühn, F.J., Heiner, I., Lückhoff, A. Pflugers Arch. (2005) [Pubmed]
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