Erythromelalgia Mutation Q875E Stabilizes the Activated State of Sodium Channel Nav1.7 [Molecular Bases of Disease]

January 9th, 2015 by Stadler, T., O'Reilly, A. O., Lampert, A.

The human voltage-gated sodium channel Nav1.7 plays a crucial role in transmission of noxious stimuli. The inherited pain disorder erythromelalgia (IEM) has been linked to Nav1.7 gain-of-function mutations. Here we show that the IEM-associated Q875E mutation located on the pore moduleof Nav1.7 produces a large hyperpolarizing shift (-18 mV) in the voltage-dependence of activation. 3D homology modelling indicates that the side chains of Q875 and the gating-charge R214 of the domain I voltage-sensor are spatially close in the channel's activated conformation. We verified this proximity by using an engineered disulphide bridge approach. The Q875E mutation introduces a negative charge that may modify the local electrical field experienced by the voltage-sensor and, upon activation, interact directly via a salt bridge with the R214 gating-charge residue. Together these processes could promote transition to, and stabilization of, the domain I voltage-sensor in the activated conformation and thus produce the observed gain-of-function.