Leaky sodium channels from voltage sensor mutations in periodic paralysis, but not paramyotonia

DG Francis, V Rybalchenko, A Struyk, SC Cannon - Neurology, 2011 - AAN Enterprises
DG Francis, V Rybalchenko, A Struyk, SC Cannon
Neurology, 2011AAN Enterprises
Background: Hypokalemic periodic paralysis (HypoPP) is associated with mutations in either
the CaV1. 1 calcium channel or the NaV1. 4 sodium channel. Some NaV1. 4 HypoPP
mutations have been shown to cause an anomalous inward current that may contribute to
the attacks of paralysis. Herein, we test whether disease-associated NaV1. 4 mutations in
previously untested homologous regions of the channel also give rise to the anomalous
current. Methods: The functional properties of mutant NaV1. 4 channels were studied with …
Background
Hypokalemic periodic paralysis (HypoPP) is associated with mutations in either the CaV1.1 calcium channel or the NaV1.4 sodium channel. Some NaV1.4 HypoPP mutations have been shown to cause an anomalous inward current that may contribute to the attacks of paralysis. Herein, we test whether disease-associated NaV1.4 mutations in previously untested homologous regions of the channel also give rise to the anomalous current.
Methods
The functional properties of mutant NaV1.4 channels were studied with voltage-clamp techniques in an oocyte expression system.
Results
The HypoPP mutation NaV1.4-R1132Q conducts an anomalous gating pore current, but the homologous R1448C mutation in paramyotonia congenita does not.
Conclusions
Gating pore currents arising from missense mutations at arginine residues in the voltage sensor domains of NaV1.4 are a common feature of HypoPP mutant channels and contribute to the attacks of paralysis.
American Academy of Neurology