1.A.4.5.12
TrpM4 of 1213 aas and 6 TMSs. Calcium-activated non selective cation channel that mediates membrane depolarization. While it is activated by increases in intracellular Ca²⁺, it is impermeable to it. It does mediate transport of monovalent cations (Na⁺ > K⁺ > Cs⁺ > Li⁺), leading to depolarize the membrane. It thereby plays a central role in  the function of cardiomyocytes, neurons from entorhinal cortex, dorsal root and vomeronasal neurons, endocrine pancreas cells, kidney epithelial cells, cochlea hair cells etc. It also participates in T-cell activation by modulating Ca²⁺ oscillations after T lymphocyte activation (Demion et al. 2007). The structure has been determined by cryo EM both with and without ATP (Guo et al. 2017). It consists of multiple transmembrane and cytosolic domains, which assemble into a three-tiered architecture. The N-terminal nucleotide-binding domain and the C-terminal coiled-coil participate in the tetrameric assembly of the channel; ATP binds at the nucleotide-binding domain to inhibit channel activity. TRPM4 has an exceptionally wide filter although it is only permeable to monovalent cations; filter residue Gln973 is essential in defining monovalent selectivity. The S1-S4 domain and the post-S6 TRP domain form the central gating apparatus that probably houses the Ca²⁺- and PtdIns(4,5)P2-binding sites (Guo et al. 2017).  TRPM4 currents are activated by micromolar concentrations of cytoplasmic Ca²⁺and progressively desensitized. Zhang et al. 2005 showed that desensitization can be explained by a loss of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P(2)) from the channels. TrpM4 interacts directly with glutamate N-methyl-D-aspartate receptor channels (NMDARs) to promote excitotoxicity. Small-molecule interface inhibitors prevent NMDAR-TRPM4 physical coupling and eliminate excitotoxicity. They are therefore neuroprotectants (Yan et al. 2020). Knockdown of the TRPM4 channel alters cardiac electrophysiology and hemodynamics in a sex- and age-dependent manner in mice (Arullampalam et al. 2023).