A sodium channel defect in hyperkalemic periodic paralysis: potassium-induced failure of inactivation.
Hyperkalemic periodic analysis (HPP) is an autosomal dominant disorder characterized by episodic weakness lasting minutes to days in association with a mild elevation in serum K+. In vitro measurements of whole-cell currents in HPP muscle have demonstrated a persistent, tetrodotoxin-sensitive Na+ current, and we have recently shown by linkage analysis that the Na+ channel alpha subunit gene may contain the HPP mutation. In this study, we have made patch-clamp recordings from cultured HPP myotubes and found a defect in the normal voltage-dependent inactivation of Na+ channels. Moderate elevation of extracellular K+ favors an aberrant gating mode in a small fraction of the channels that is characterized by persistent reopenings and prolonged dwell times in the open state. The Na+ current, through noninactivating channels, may cause the skeletal muscle weakness in HPP by depolarizing the cell, thereby inactivating normal Na+ channels, which are then unable to generate an action potential. Thus the dominant expression of HPP is manifest by inactivation of the wild-type Na+ channel through the influence of the mutant gene product on membrane voltage.
Cannon
S C
SC
Department of Neurology, Massachusetts General Hospital, Boston.
Brown
R H
RH
Corey
D P
DP
D004594:Electrophysiology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006947:Hyperkalemia / Q000150:complications*; D015640:Ion Channel Gating; D007700:Kinetics; D009132:Muscles / Q000378:metabolism; D010245:Paralyses, Familial Periodic / Q000150:complications*; D011188:Potassium / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*
D015222:Sodium Channels; D011188:Potassium