Alternative titles; symbols
HGNC Approved Gene Symbol: TRPM2
Cytogenetic location: 21q22.3 Genomic coordinates (GRCh38) : 21:44,353,621-44,442,644 (from NCBI)
TRPM2 belongs to the melastatin (TRPM1; 603576)-related transient receptor (TRPM) channel family. TRPMs are Ca(2+)-permeable cation channels localized predominantly to the plasma membrane. The structural machinery of TRPM channels includes intracellular N and C termini, 6 transmembrane segments, and a pore region between segments 5 and 6. The N-terminal domain has a conserved region, and the C-terminal domain contains a TRP motif, a coiled-coil region, and, in TRPM2, an enzymatic NUDT9 (606022) homologous domain. TRPM2 is involved in oxidative stress-induced cell death and inflammation processes, and it has a major role in lipopolysaccharide-provoked cytokine production (summary by Du et al. (2009) and Farooqi et al. (2011)).
Using exon trapping on a contig from chromosome 21q22.3, Kudoh et al. (1997) isolated an exon whose deduced amino acid sequence showed similarity to the sequences of human TRPC and Drosophila trp proteins. Nagamine et al. (1998) isolated human fetal brain and caudate nucleus cDNAs corresponding to the exon and its parent gene. The deduced 1,503-amino acid protein, designated TRPC7, is 22.9% identical to human TRPC1 (602343), 21.2% identical to human TRPC3 (602345), and 22.6% identical to Drosophila trp. TRPC7 contains 7 predicted membrane-spanning domains. Northern blot analysis of human tissues detected a 6.5-kb TRPC7 transcript predominantly in fetal and adult brain, where it was expressed in several regions. In caudate nucleus and putamen, a putative 5.5-kb alternatively spliced TRPC7 product was also detected.
By RT-PCR of HL60 human myeloid leukemia cell total RNA, Wehage et al. (2002) cloned an LTRPC2 splice variant that encodes a protein with 20- and 34-amino acid deletions in its cytoplasmic N- and C-terminal domains, respectively, compared with full-length LTRPC2 (Nagamine et al., 1998). Using PCR, they identified this variant and variants encoding proteins with only the N- or C-terminal deletion in neutrophil granulocytes and HL60 cells.
By PCR of a bone marrow cDNA library, Zhang et al. (2003) identified a short variant of TRPM2, called TRPM2S, in which alternative splicing of the 3-prime end of intron 16 introduces a premature stop codon. The deduced 845-amino acid protein is identical to the first 845 amino acids of full-length TRPM2 and includes the first 2 transmembrane spans, but it lacks the 4 C-terminal transmembrane spans and the putative pore region. PCR analysis showed that TRPM2 was expressed in all hematopoietic cell lines examined, with weaker expression in primary human erythroblasts and HEK293 cells. TRPM2S was detected in all hematopoietic cell lines examined. Immunohistochemical analysis showed localization of both TRPM2S and full-length TRPM2 on or near the plasma membrane.
Uemura et al. (2005) cloned the 5.5-kb TRPM2 splice variant, which they called short striatal form (SSF)-TRPM2 due to its expression in striatum only. In contrast, PCR analysis detected the full-length 6.5-kb TRPM2 transcript in all tissues and specific brain regions examined. The first exon of SSF-TRPM2 is an extended form of TRPM2 exon 5, and the deduced 1,289-amino acid SSF-TRPM2 protein is translated from the second met codon (met215) of full-length TRPM2. SSF-TRPM2 contains the 6-transmembrane domain, including the pore region, followed by a coiled-coil region and C-terminal NUDIX domain. Immunofluorescence microscopy detected both full-length TRPM2 and SSF-TRPM2 at the plasma membrane of transfected HEK293 cells. Western blot analysis detected full-length TRPM2 at an apparent molecular mass of 174.5 kD and SSF-TRPM2 at an apparent molecular mass of 150.6 kD. Uemura et al. (2005) did not detect Ssf-Trpm2 in any mouse tissues examined, including striatum.
Du et al. (2009) noted that the N-terminal region of TRPM2 contains a putative calmodulin (see CALM1; 114180)-binding IQ motif.
Nagamine et al. (1998) determined that the TRPC7 gene has 32 exons spanning approximately 90 kb.
By 5-prime RACE, Uemura et al. (2005) identified an additional 5-prime exon in the TRPM2 gene. They concluded that the TRPM2 gene contains 33 exons and spans 93 kb. The upstream exon is contained within a CpG island. TRPM2 has an upstream promoter region for expression of full-length TRPM2 and an internal promoter region for expression of SSF-TRPM2. The mouse Trpm2 gene contains 34 exons and spans about 61 kb, but it has only an upstream promoter region that is less GC-rich than the upstream promoter region of human TRPM2.
Cryoelectron Microscopy
Wang et al. (2018) reported cryoelectron microscopy structures of human TRPM2 alone, with adenosine diphosphate (ADP) ribose (ADPR), and with ADPR and Ca(2+). The NUDT9 homology domain forms both intra- and intersubunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state, but undergoes conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the intersubunit interaction. The binding of Ca(2+) further engages transmembrane helices and the conserved TRP helix to cause conformational changes at the MHR arm and the lower gating pore to potentiate channel opening. Wang et al. (2018) concluded that their findings explained the molecular mechanism of concerted TRPM2 gating by ADPR and Ca(2+) and provided insights into the gating mechanism of other TRP channels.
Huang et al. (2018) reported the cryoelectron microscopy structures of zebrafish Trpm2 in the apo resting (closed) state and in the ADPR/Ca(2+)-bound active (open) state, in which the characteristic NUDT9-H domains hang underneath the MHR1/2 domain. Huang et al. (2018) identified an ADPR-binding site located in the bilobed structure of the MHR1/2 domain.
Using a cosmid/BAC contig, Kudoh et al. (1997) mapped the TRPM2 gene to chromosome 21q22.3.
Perraud et al. (2001) demonstrated that a 350-amino acid protein, designated NUDT9 (606022), and a homologous domain (NUDT9 homology domain) near the C terminus of the LTRPC2 putative cation channel both function as specific ADP-ribose pyrophosphatases. Whole-cell and single-channel analysis of HEK293 cells expressing LTRPC2 showed that LTRPC2 functions as a calcium-permeable cation channel that is specifically gated by free ADP-ribose. The expression of native LTRPC2 transcripts is detectable in many tissues, including the U937 monocyte cell line, in which ADP-ribose induces large cation currents that closely match those mediated by recombinant LTRPC2. Perraud et al. (2001) concluded that intracellular ADP-ribose regulates calcium entry into cells that express LTRPC2.
Using RT-PCR, Sano et al. (2001) determined that TRPC7 is the most abundantly expressed long TRPC in peripheral blood and in some blood cell lines. Sequence analysis indicated that TRPC7 has a C-terminal MutT motif, which is predicted to participate in nucleotide hydrolase activity. Using whole-cell patch-clamp analysis, Sano et al. (2001) found that ADP ribose and beta-NAD evoked an inward current whereas other nucleotides had no effect. The response to ADP ribose was immediate, while that to beta-NAD was delayed. TRPC7 activation by these nucleotides did not depend on cytoplasmic or membrane components, but may be regulated by intracellular ATP levels. Sano et al. (2001) concluded that TRPC7 is a cation current channel and a calcium influx system for immunocytes.
Hara et al. (2002) reported that LTRPC2 is activated by micromolar levels of H2O2 and agents that produce reactive oxygen/nitrogen species. This sensitivity of LTRPC2 to redox state modifiers was attributable to an agonistic binding of beta-nicotinamide adenine dinucleotide to the MutT motif. Arachidonic acid and calcium were important positive regulators for LTRPC2. Heterologous LTRPC2 expression conferred susceptibility to death on HEK cells. Antisense oligonucleotide experiments revealed physiologic involvement of native LTRPC2 in H2O2- and TNF-alpha (191160)-induced calcium influx and cell death. Thus, LTRPC2 represents an important intrinsic mechanism that mediates calcium and sodium overload in response to disturbance of redox state in cell death.
By assaying transfected HEK293 cells, Wehage et al. (2002) showed that H2O2 and intracellular ADP-ribose induced LTRPC2-mediated currents carried by monovalent cations and calcium. H2O2, but not ADP-ribose, induced a second delayed rise in calcium concentration. The LTRPC2 isoform with a deletion in the C-terminal domain was stimulated by H2O2 like the full-length isoform, but it was not activated by ADP-ribose. The LTRPC2 isoforms with a deletion in the N-terminal domain, either with or without the C-terminal deletion, were not stimulated by H2O2 or ADP-ribose, suggesting that isoforms with the N-terminal deletion do not form functional channels. No TRPM2 isoform responded to NAD.
Using coimmunoprecipitation analysis, Zhang et al. (2003) showed that TRPM2S interacted directly with full-length TRPM2. TRPM2S did not function as a calcium channel in transfected HEK293 cells, but it inhibited H2O2-induced channel activity of full-length TRPM2. H2O2 treatment of cells expressing full-length TRPM2 caused a dose-dependent decrease in cell viability due to increased apoptosis, and coexpression of TRPM2S offered some protection against oxidative stress.
Using transfected HEK293 cells, Uemura et al. (2005) found that SSF-TRPM2 mediated slightly weaker H2O2-activated calcium currents compared with full-length TRPM2.
Vazquez et al. (2006) showed that endogenous Trpc7 in an avian B-cell line behaved as a diacylglycerol-activated, nonselective cation channel that required inositol trisphosphate (IP3) receptors (see 147265) for activity. Overexpression of Trpc7 produced a channel with altered kinetic properties that became independent of IP3 receptors.
Using a human monocyte line, Yamamoto et al. (2008) showed that Ca(2+) influx through TRPM2 controlled H2O2-induced expression of CXCL8 (146930) and activated PYK2 (PTK2B; 601212) in an ERK (see MAPK1; 176948)- and NFKB (see 164011)-dependent manner. They concluded that TRPM2 Ca(2+) influx controls the reactive oxygen species-induced signaling cascade responsible for chemokine production, which aggravates inflammation.
Using whole-cell and single-channel recordings of transfected HEK293 cells, Du et al. (2009) showed that elevated intracellular calcium concentration activated full-length TRPM2, but with a current amplitude less than that elicited by ADP-ribose plus elevated intracellular calcium. TRPM2 isoforms with deletions in the N-terminal and/or C-terminal domains, which are insensitive to ADP-ribose and H2O2, were also activated by elevated intracellular calcium concentrations. IP3 receptor activation induced calcium release that was capable of activating TRPM2. Mutation analysis showed that the calmodulin-binding IQ motif of TRPM2 was essential for calcium- and ADP-ribose/calcium-mediated TRPM2 activation, suggesting that binding to calcium and calmodulin is required for TRPM2 channel activity.
Tan and McNaughton (2016) used calcium imaging to identify a population of thermally sensitive somatosensory neurons which do not express any of the known thermally activated TRP channels. They then used a combination of calcium imaging, electrophysiology, and RNA sequencing to show that the ion channel generating heat sensitivity in these neurons is TRPM2. Autonomic neurons, usually thought of as exclusively motor, also express TRPM2 and respond directly to heat. Mice in which TRPM2 had been genetically deleted showed a striking deficit in their sensation of nonnoxious warm temperatures, consistent with the idea that TRPM2 initiates a 'warm' signal which drives cool-seeking behavior.
Song et al. (2016) demonstrated that the ion channel TRPM2 is a temperature sensor in a subpopulation of hypothalamic neurons. TRPM2 limits the fever response and may detect increased temperatures to prevent overheating. Furthermore, chemogenetic activation and inhibition of hypothalamic TRPM2-expressing neurons in vivo decreased and increased body temperature, respectively. Such manipulation may allow analysis of the beneficial effects of altered body temperature on diverse disease states. Song et al. (2016) concluded that identification of a functional role for TRP channels in monitoring internal body temperature should promote further analysis of molecular mechanisms governing thermoregulation and foster the genetic dissection of hypothalamic circuits involved with temperature homeostasis.
McQuillin et al. (2006) fine mapped chromosome 21q22.3 using 30 genetic markers in 600 subjects with bipolar disorder (see 125480) and 450 ancestrally matched supernormal controls. Allelic association with D21S171 (p = 0.016), rs1556314 (p = 0.008), and rs1785467 (p = 0.025) was observed. A test of association with a 3-locus haplotype across a susceptibility region was significant with a permutation test (p = 0.011), and a 2-SNP haplotype was also significantly associated with bipolar disorder (p = 0.01). The 2 brain-expressed genes present in the associated region, TRPM2 and C21ORF29 (612920), were sequenced from subjects who had inherited the associated marker alleles. The rs1556314 polymorphism in exon 11 of TRPM2, which causes an asp543-to-glu (D543E) change, showed the strongest association with bipolar disorder (p = 0.008); see MAFD3 (609633). McQuillin et al. (2006) noted that deletion of exon 11 is known to cause dysregulation of cellular calcium homeostasis in response to oxidative stress.
All proteins of the transient receptor potential (TRP) channel family display topology of 6 transmembrane segments that is shared with some voltage-gated channels and the cyclic nucleotide-gated channels. The TRP channels can be divided on the basis of their homology into 3 TRP channel subfamilies: short (S), long (L), and osm (O). Harteneck et al. (2000) suggested that this subdivision also can be made according to channel function. Thus, the STRPC family, which includes Drosophila TRP and TRPL and the mammalian homologs TRPC1-7, is a family of calcium-permeable cation channels that are activated subsequent to receptor-mediated stimulation of different isoforms of phospholipase C. Members of the OTRPC family are calcium-permeable channels involved in pain transduction (vanilloid and vanilloid-like receptors), epithelial calcium transport, and, at least in C. elegans, in chemo-, mechano-, and osmoregulation.
Yamamoto et al. (2008) found that monocytes from Trpm2-deficient mice had impaired production of Cxcl2, the functional homolog of CXCL8 in mice. In the dextran sulfate sodium-induced colitis inflammation model, Cxcl2 expression, neutrophil infiltration, and ulceration were attenuated by Trpm2 disruption. Yamamoto et al. (2008) concluded that TRPM2 has a major role in the progressive severity of inflammation.
Du, J., Xie, J., Yue, L. Intracellular calcium activates TRPM2 and its alternative spliced isoforms. Proc. Nat. Acad. Sci. 106: 7239-7244, 2009. [PubMed: 19372375] [Full Text: https://doi.org/10.1073/pnas.0811725106]
Farooqi, A. A., Javeed, M. K., Javed, Z., Riaz, A. M., Mukhtar, S., Minhaj, S., Abbas, S., Bhatti, S. TRPM channels: same ballpark, different players, and different rules in immunogenetics. Immunogenetics 63: 773-787, 2011. [PubMed: 21932052] [Full Text: https://doi.org/10.1007/s00251-011-0570-4]
Hara, Y., Wakamori, M., Ishii, M., Maeno, E., Nishida, M., Yoshida, T., Yamada, H., Shimizu, S., Mori, E., Kudoh, J., Shimizu, S., Kurose, H., Okada, Y., Imoto, K., Mori, Y. LTRPC2 Ca(2+)-permeable channel activated by changes in redox status confers susceptibility to cell death. Molec. Cell 9: 163-173, 2002. [PubMed: 11804595] [Full Text: https://doi.org/10.1016/s1097-2765(01)00438-5]
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Huang, Y., Winkler, P. A., Sun, W., Lu, W., Du, J. Architecture of the TRPM2 channel and its activation mechanism by ADP-ribose and calcium. Nature 562: 145-149, 2018. [PubMed: 30250252] [Full Text: https://doi.org/10.1038/s41586-018-0558-4]
Kudoh, J., Nagamine, K., Asakawa, S., Abe, I., Kawasaki, K., Maeda, H., Tsujimoto, S., Minoshima, S., Ito, F., Shimizu, N. 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: 45-52, 1997. [PubMed: 9179495] [Full Text: https://doi.org/10.1093/dnares/4.1.45]
McQuillin, A., Bass, N. J., Kalsi, G., Lawrence, J., Puri, V., Choudhury, K., Detera-Wadleigh, S. D., Curtis, D., Gurling, H. M. D. Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3. Molec. Psychiat. 11: 134-142, 2006. [PubMed: 16205735] [Full Text: https://doi.org/10.1038/sj.mp.4001759]
Nagamine, K., Kudoh, J., Minoshima, S., Kawasaki, K., Asakawa, S., Ito, F., Shimizu, N. Molecular cloning of a novel putative Ca(2+) channel protein (TRPC7) highly expressed in brain. Genomics 54: 124-131, 1998. [PubMed: 9806837] [Full Text: https://doi.org/10.1006/geno.1998.5551]
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. ADP-ribose gating of the calcium-permeable LTRPC2 channel revealed by Nudix motif homology. Nature 411: 595-599, 2001. [PubMed: 11385575] [Full Text: https://doi.org/10.1038/35079100]
Sano, Y., Inamura, K., Miyake, A., Mochizuki, S., Yokoi, H., Matsushime, H., Furuichi, K. Immunocyte Ca(2+) influx system mediated by LTRPC2. Science 293: 1327-1330, 2001. [PubMed: 11509734] [Full Text: https://doi.org/10.1126/science.1062473]
Song, K., Wang, H., Kamm, G. B., Pohle, J., de Castro Reis, F., Heppenstall, P., Wende, H., Siemens, J. The TRPM2 channel is a hypothalamic heat sensor that limits fever and can drive hypothermia. Science 353: 1393-1398, 2016. [PubMed: 27562954] [Full Text: https://doi.org/10.1126/science.aaf7537]
Tan, C.-H., McNaughton, P. A. The TRPM2 ion channel is required for sensitivity to warmth. Nature 536: 460-463, 2016. [PubMed: 27533035] [Full Text: https://doi.org/10.1038/nature19074]
Uemura, T., Kudoh, J., Noda, S., Kanba, S., Shimizu, N. 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: 1232-1243, 2005. [PubMed: 15708008] [Full Text: https://doi.org/10.1016/j.bbrc.2005.01.086]
Vazquez, G., Bird, G. St. J., Mori, Y., Putney, J. W., Jr. Native TRPC7 channel activation by an inositol trisphosphate receptor-dependent mechanism. J. Biol. Chem. 281: 25250-25258, 2006. [PubMed: 16822861] [Full Text: https://doi.org/10.1074/jbc.M604994200]
Wang, L., Fu, T.-M., Zhou, Y., Xia, S., Greka, A., Wu, H. Structures and gating mechanism of human TRPM2. Science 362: eaav4809, 2018. Note: Electronic Article. [PubMed: 30467180] [Full Text: https://doi.org/10.1126/science.aav4809]
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. 277: 23150-23156, 2002. [PubMed: 11960981] [Full Text: https://doi.org/10.1074/jbc.M112096200]
Yamamoto, S., Shimizu, S., Kiyonaka, S., Takahashi, N., Wajima, T., Hara, Y., Negoro, T., Hiroi, T., Kiuchi, Y., Okada, T., Kaneko, S., Lange, I., Fleig, A., Penner, R., Nishi, M., Takeshima, H., Mori, Y. TRPM2-mediated Ca2+ influx induces chemokine production in monocytes that aggravates inflammatory neutrophil infiltration. Nature Med. 14: 738-747, 2008. [PubMed: 18542050] [Full Text: https://doi.org/10.1038/nm1758]
Zhang, W., Chu, X., Tong, Q., Cheung, J. Y., Conrad, K., Masker, K., Miller, B. A. A novel TRPM2 isoform inhibits calcium influx and susceptibility to cell death. J. Biol. Chem. 278: 16222-16229, 2003. [PubMed: 12594222] [Full Text: https://doi.org/10.1074/jbc.M300298200]