| Primary Identifier | IPR044564 | Type | Domain |
| Short Name | Na_chnl_inactivation_gate |
| description | Voltage-dependent sodium channels are transmembrane (TM) proteins responsible for the depolarising phase of the action potential in mostelectrically excitable cells []. They may exist in 3 states []: the resting state, where the channel is closed; the activated state, where the channel is open; and the inactivated state, where the channel is closed and refractory to opening. Several different structurally and functionally distinct isoforms are found in mammals, coded for by a multigene family, these being responsible for the different types of sodium ion currents found in excitable tissues.There are nine pore-forming alpha subunit of voltage-gated sodium channels consisting of four membrane-embedded homologous domains (I-IV), each consisting of six α-helical segments (S1-S6), three cytoplasmic loops connecting the domains, and a cytoplasmic C-terminal tail. The S6 segments of the four domains form the inner surface of the pore, while the S4 segments bear clusters of basic residues that constitute the channel's voltage sensors [, , ].This domain represents the cytoplasmic loop connecting domains III and IV of the alpha subunits of voltage-gated sodium channels. It forms the channel inactivation gate, acting through a hinged lid mechanism, which is responsible for fast inactivation of the channel and it is essential for proper physiological function [, ]. This domain contains the highly conserved hydrophobic isoleucine-phenylalanine-methionine (IFM) triad, essential for the fast inactivation mechanism. In particular the phenylalanine residue is suggested to bind to an inactivation gate receptor that causes the loop to occlude the channel pore during the inactivation process. Mutation of this residue causes a severe impairment of the inactivation process, while full mutation of the triad abolishes completely inactivation []. |
