1.A.4.5.4
Intracellular Ca²⁺-activated nonselective monovalent cation (Na⁺ and K⁺) channel (non-permeable to Ca²⁺), TRPM4b, involved in inherited cardiac arrhythmia syndromes (Amarouch and El Hilaly 2020). It interacts with the TRPC3 channel and suppresses store-operated Ca⁺ entry (Park et al., 2008).  Contributes to the mammalian atrial action potential (Simard et al. 2013). TRPM4 is widely expressed and is associated with a variety of cardiovascular disorders. Autzen et al. 2018 presented two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3-angstrom resolution, as determined by single-particle cryo-electron microscopy. These structures, with and without calcium bound, reveal the general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening (Autzen et al. 2018). TRPM4 functions as a limiting factor for antigen evoked calcium rise in connective tissue type mast cells, and concurrent translocation of TRPM4 into the plasma membrane is part of this mechanism (Rixecker et al. 2016).  Gain-of-function mutations in the TRPM4 activation gate caused progressive symmetric erythrokeratoderma (Wang et al. 2018). Substitution of the 4 residue motif, EPGF, with other amino acids reduced cation binding affinity. Analysis of the human TRPM4 structure indicated that EPGF is located externally to the channel pore (Wei et al. 2022).