title: Hyperkalemic periodic paralysis M1592V mutation modifies activation in human skeletal muscle Na+ channel.
abstract: 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 beta1-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.
authors.affiliation: Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Chile, Casilla 138-11, Santiago, Chile.
authors.forename: C V
authors.initials: CV
authors.lastname: Rojas
authors.forename: A
authors.initials: A
authors.lastname: Neely
authors.forename: G
authors.initials: G
authors.lastname: Velasco-Loyden
authors.forename: V
authors.initials: V
authors.lastname: Palma
authors.forename: M
authors.initials: M
authors.lastname: Kukuljan
mesh_terms: D000818:Animals; D004553:Electric Conductivity; D005260:Female; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D006947:Hyperkalemia / Q000150:complications*; D015640:Ion Channel Gating / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation / Q000502:physiology*; D009865:Oocytes; D010243:Paralysis / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D010507:Periodicity; D012016:Reference Values; D015222:Sodium Channels / Q000378:metabolism* / Q000502:physiology; D014982:Xenopus laevis
chemical_list: D015222:Sodium Channels