title: Domain III S4 in closed-state fast inactivation: insights from a periodic paralysis mutation.
abstract: Heterologous expression of sodium channel mutations in hypokalemic periodic paralysis reveals 2 variants on channel dysfunction. Charge-reducing mutations of voltage sensing S4 arginine residues alter channel gating as typically studied with expression in mammalian cells. These mutations also produce leak currents through the voltage sensor module, as typically studied with expression in Xenopus oocytes. DIIIS4 mutations at R3 in the skeletal muscle sodium channel produce gating defects and omega current consistent with the phenotype of reduced excitability. Here, we confirm DIIIS4 R3C gating defects in the oocyte expression system for fast inactivation and its recovery. We provide novel data for the effects of the cysteine mutation on voltage sensor movement, to further our understanding of sodium channel defects in hypokalemic periodic paralysis. Gating charge movement and its remobilization are selectively altered by the mutation at hyperpolarized membrane potential, as expected with reduced serum potassium.
authors.affiliation: a Department of Biological Sciences ; Idaho State University ; Pocatello , ID USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Groome
authors.forename: Karin
authors.initials: K
authors.lastname: Jurkat-Rott
authors.forename: Frank
authors.initials: F
authors.lastname: Lehmann-Horn
mesh_terms: D000818:Animals; D020514:Hypokalemic Periodic Paralysis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D014982:Xenopus laevis
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel
keywords: fast inactivation; gating charge; hypokalemic periodic paralysis; sodium channel; voltage sensor