Title: Gating defects of a novel Na+ channel mutant causing hypokalemic periodic paralysis.

Authors: Thomas Carle, Loïc Lhuillier, Sandrine Luce, Damien Sternberg, Olivier Devuyst, Bertrand Fontaine, Nacira Tabti

Journal, date & volume: Biochem. Biophys. Res. Commun., 2006 Sep 22 , 348, 653-61

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16890191

Abstract
Hypokalemic periodic paralysis type 2 (hypoPP2) is an inherited skeletal muscle disorder caused by missense mutations in the SCN4A gene encoding the alpha subunit of the skeletal muscle Na+ channel (Nav1.4). All hypoPP2 mutations reported so far target an arginine residue of the voltage sensor S4 of domain II (R672/G/H/S). We identified a novel hypoPP2 mutation that neutralizes an arginine residue in DIII-S4 (R1132Q), and studied its functional consequences in HEK cells transfected with the human SCN4A cDNA. Whole-cell current recordings revealed an enhancement of both fast and slow inactivation, as well as a depolarizing shift of the activation curve. The unitary Na+ conductance remained normal in R1132Q and in R672S mutants, and cannot therefore account for the reduction of Na+ current presumed in hypoPP2. Altogether, our results provide a clear evidence for the role of R1132 in channel activation and inactivation, and confirm loss of function effects of hypoPP2 mutations leading to muscle hypoexcitability.