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Am J Physiol Cell Physiol 276: C259-C266, 1999;
0363-6143/99 $5.00
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Vol. 276, Issue 1, C259-C266, January 1999

Hyperkalemic periodic paralysis M1592V mutation modifies activation in human skeletal muscle Na+ channel

Cecilia V. Rojas1, Alan Neely2, Gabriela Velasco-Loyden1, Verónica Palma3, and Manuel Kukuljan3

1 Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Chile, Casilla 138-11, Santiago; and 3 Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70005-7, Santiago, Chile; and 2 Department of Physiology, Texas Tech University Health Sciences Center, Lubbock, Texas 79430

Mutations in the human skeletal muscle Na+ channel underlie the autosomal dominant disease hyperkalemic periodic paralysis (HPP). Muscle fibers from affected individuals exhibit sustained Na+ currents thought to depolarize the sarcolemma and thus inactivate normal Na+ channels. We expressed human wild-type or M1592V mutant alpha -subunits with the beta 1-subunit in Xenopus laevis oocytes and recorded Na+ currents using two-electrode and cut-open oocyte voltage-clamp techniques. The most prominent functional difference between M1592V mutant and wild-type channels is a 5- to 10-mV shift in the hyperpolarized direction of the steady-state activation curve. The shift in the activation curve for the mutant results in a larger overlap with the inactivation curve than that observed for wild-type channels. Accordingly, the current through M1592V channels displays a larger noninactivating component than does that through wild-type channels at membrane potentials near -40 mV. The functional properties of the M1592V mutant resemble those of the previously characterized HPP T704M mutant. Both clinically similar phenotypes arise from mutations located at a distance from the putative voltage sensor of the channel.

sodium current; ion channel; neuromuscular disease; gating; Xenopus oocytes


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