1.A.4.5.5
ADP-ribose/NAD/pyrimidine nucleotide-gated Ca²⁺ permeable, cation nonselective, long transient receptor potential channel-2, LTRPC2; Melastatin 2; TRPM2 (ATP inhibitable). The 3-D structure resembles a swollen bell shaped structure (Maruyama et al., 2007). It can be converted to an anion-selective channel by introducing a lysyl residue in TMS 6 (Kuhn et al., 2007). It transports Ca²⁺ and Mg²⁺ with equal facility (Xia et al., 2008).  Four Ca²⁺ ions activate TRPM2 channels by binding in deep crevices near the pore but intracellularly of the gate (Csanády and Törocsik, 2009). Protons also regulate activity (Starkus et al., 2010). It is present in the plasma membrane and lysosomes, and plays a role in ROS-induced inflammatory processes and cell death. Melastatin is required for innate immunity against Listeria monocytogenes (Knowles et al., 2011). It functions in pathogen-evoked phagocyte activation, postischemic neuronal apoptosis, and glucose-evoked insulin secretion, by linking these cellular responses to oxidative stress (Tóth and Csanády, 2012).  Pore collapse upon prolonged stimulation underlies irreversible inactivation (Tóth and Csanády 2012).  TRPM2 is preferentially expressed in cells of the myeloid lineage and modulates signaling pathways converging into NF-kB but does not seem to play a major role in myeloid leukemogenesis. Its loss does not augment the cytotoxicity of standard AML chemotherapeutic agents (Haladyna et al. 2016).  TrpM2, expressed in hypothalamic neurons in the brain is a thermosensitive, redox-sensitive channel, required for thermoregulation.  It regulates body temperature, limiting fever and driving hypothermia (Song et al. 2016). Tseng et al. 2016 suggested a mechanistic link between TRPM2-mediated Ca²⁺ influx and p47 phox signaling to induce excess ROS production and TXNIP-mediated NLRP3 inflammasome activation under high gllucose in Type 2 diabetes Mellitus. The cryoEM strcuture reveals a C-terminal NUDT9 homology (NUDT9H) domain responsible for binding ADP-ribose(ADPR) (Wang et al. 2018). Both ADPR and Ca²⁺ are required for TRPM2 activation, and structures with ADPR and Ca²⁺ show both intra- and inter-subunit interactions with the N-terminal TRPM homology region (MHR1/2/3) in the apo state, but undergoing conformational changes upon ADPR binding, resulting in rotation of MHR1/2 and disruption of the inter-subunit interaction. Ca²⁺ binding 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). Consecutive structural rearrangements and channel activation are induced by binding of ADPR in two indispensable locations, and the binding of Ca²⁺ in the transmembrane domain (Huang et al. 2019). An N-terminal TRPC2 splice variant of 213 aas inhibits calcium influx (Chu et al. 2005). An antogonists of channel function has been identified (Cruz-Torres et al. 2020). A point mutant of TrpM2 (rs93315) has been identified as a risk factor for bipolar disorder (Mahmuda et al. 2020). Two gates orchestrate the opening of human TRPM2 (Rish et al. 2022). Protein kinase C (PKC)-mediated phosphorylation of TRPM2 Thr738 counteracts the effect of cytosolic Ca²⁺ and elevates the temperature threshold (Kashio et al. 2022). Citronellal suppresses the expression of NHE1 and TPRM2, alleviates oxidative stress-induced mitochondrial damage, and imposes a protective effect on endothelial dysfunction in type 2 diabetes mellitus rats (Yin et al. 2022). Key residues, E829 and R845, are involved in TRPM2 channel gating (Luo et al. 2022).  TRPM2 is a prognostic factor correlated with immune infiltration in ovarian cancer (Huang et al. 2023). The TRPM2 ion channel regulates metabolic and thermogenic adaptations in adipose tissue of cold-exposed mice (Benzi et al. 2023).