Gating defects of a novel Na super(+) channel mutant causing hypokalemic periodic paralysis

• Published in: Biochemical and biophysical research communications 2006-09, Vol.348 (2), p.653-661
• Main Authors: Carle, T, Lhuillier, L, Luce, S, Sternberg, D, Devuyst, O, Fontaine, B, Tabti, N
• Format: Article
• Language: English
• ISSN: 0006-291X
• DOI: 10.1016/j.bbrc.2006.07.101

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 super(+) 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 super(+) conductance remained normal in R1132Q and in R672S mutants, and cannot therefore account for the reduction of Na super(+) 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.