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

• These new findings are invaluable to further study the regulation of TRPM2 gene expression and to examine the possible involvement of the TRPM2 gene in the pathophysiology of bipolar disorder [5].

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

• Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels [11].
• When these are analyzed in heterologous overexpression experiments, TRPM2 is the only cation channel with characteristic properties that can be used as fingerprint to provide functional evidence for its expression in neutrophil granulocytes [13].
• As cells transfected with TRPM2, neutrophil granulocytes display non-selective cation currents and typical channel activity evoked by intracellular ADP-ribose and NAD [13].
• 5. ADPR-induced currents in human U937 cells, endogeneously expressing TRPM2 protein, were fully suppressed by 20 microM ACA [14].
• Expression of TRPM2 in the plasma membrane of Jurkat T cells was demonstrated by reverse transcription-PCR, Western blot, and immunofluorescence [16].

Associations of TRPM2 with chemical compounds

• Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels [8].
• TRPM2 channel currents in inside-out patches showed a strong requirement for Ca(2+) at the intracellular face of the membrane [17].
• In this study we investigated the calcium dependence of human TRPM2 expressed under a tetracycline-dependent promoter in HEK-293 cells [17].
• These results taken together suggest that the cysteine residues in the pore region are obligatory for TRPM2 channel function [18].
• We investigated the modulation of TRPM2 activity by N-(p-amylcinnamoyl)anthranilic acid (ACA) [14].
• The lysine in S6 was responsible for the anion selectivity; insertion of a lysine into corresponding sites within S6 of either TRPM2 or TRPM8 created anion channels that were activated by ADPR (TRPM2 I1045K) or by cold temperatures (TRPM8 V976K) [19].

Regulatory relationships of TRPM2

• TRPM2 is a Ca(2+)-permeable channel activated by oxidative stress or TNF-alpha, and TRPM2 activation confers susceptibility to cell death [20].
• We studied the role of TRPC7 in G protein-activated signaling in HEK293 cells and cultured cardiomyocytes in vitro transfected with FLAG-tagged TRPC7 cDNA and in Dahl salt-sensitive rats with heart failure in vivo [21].

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

• In this study, we investigated the functional role of two conserved cysteine residues (at positions 996 and 1008) in the putative pore region of the human TRPM2 by site-directed mutagenesis, combined with electrophysiological and biochemical approaches [18].
• Molecular cloning of a novel putative Ca2+ channel protein (TRPC7) highly expressed in brain [1].
• Northern blot analysis indicated that the TRPC7 gene is highly expressed as a 6.5-kb transcript in brain [1].
• Moreover, RT-PCR analysis showed that TRPM2 was abundantly expressed in CRI-G1 cells, suggesting that the ADP-ribose-gated channel represents the native TRPM2 channel in CRI-G1 cells [10].
• TRPM2 is likely to be a key player in several signalling pathways, mediating cell death in response to oxidative stress or in reperfusion injury [27].

References