Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na_V1.7.

ABSTRACT: Gain-of-function mutations in voltage-gated sodium channel Na_V1.7 cause severe inherited pain syndromes, including inherited erythromelalgia (IEM). The structural basis of these disease mutations, however, remains elusive. Here, we focused on three mutations that all substitute threonine residues in the alpha-helical S4-S5 intracellular linker that connects the voltage sensor to the pore: Na_V1.7/I234T, Na_V1.7/I848T, and Na_V1.7/S241T in order of their positions in the amino acid sequence within the S4-S5 linkers. Introduction of these IEM mutations into the ancestral bacterial sodium channel Na_VAb recapitulated the pathogenic gain-of-function of these mutants by inducing a negative shift in the voltage dependence of activation and slowi

SUBMITTER: Wisedchaisri G 

PROVIDER: S-EPMC10083536 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature