TY - JOUR
T1 - A sodium channel defect in hyperkalemic periodic paralysis
T2 - Potassium-induced failure of inactivation
AU - Cannon, Stephen C.
AU - H. Brown Jr., Robert
AU - Corey, David P.
N1 - Funding Information:
This work was supported by a fellowship from the Charles A. Dana foundation (S. C. C.) and by the Cecil B. Day Foundation (R. H. B.), the Pierre L. de Bourgknecht A. L. S. Foundation (R. H. B.), the Muscular Dystrophy Association (R. H. B.), and the Howard Hughes Medical Institute (D. P. C.). Dr. Olga Hardiman kindly assisted in dissociatingthe HPP muscle biopsyforculture. The authors appreciate the efforts of Joseph B. Martin to create an environment that continues to encourage collaboration of this sort.
PY - 1991/4
Y1 - 1991/4
N2 - 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 α 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.
AB - 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 α 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.
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U2 - 10.1016/0896-6273(91)90064-7
DO - 10.1016/0896-6273(91)90064-7
M3 - Article
C2 - 1849724
AN - SCOPUS:0025774566
SN - 0896-6273
VL - 6
SP - 619
EP - 626
JO - Neuron
JF - Neuron
IS - 4
ER -