title: K-aggravated myotonia mutations at residue G1306 differentially alter deactivation gating of human skeletal muscle sodium channels.
abstract: Fast inactivation and deactivation gating were compared between wild-type human voltage-gated skeletal muscle sodium channel (hNaV1.4) and potassium-aggravated myotonia (PAM) mutations G1306A, G1306E, and G1306V. Cell-attached macropatches were used to compare wild-type and PAM-gating properties in normal extracellular K+ (4 mM), decreased K+ (1 mM), and increased K+ (10 mM). G1306E/A increased the apparent valence of the conductance (g(V)) curve. Compared to hNaV1.4, the steady-state inactivation (h infinity) curve was depolarized for G1306E/A but hyperpolarized by G1306V, and this mutation increased apparent valence. G1306A/E slowed the rate of current rise towards peak activation. G1306V slowed open-state deactivation, inactivated-state deactivation, and recovery from fast inactivation. G1306A/E abbreviated open-state deactivation at negative commands. These mutants slowed open-state deactivation at more positive commands, at voltages for which fast inactivation might influence tail current decay. G1306E abbreviated recovery delay without affecting recovery rate. Low K+ increased peak current in hNaV1.4 and in G1306V. For G1306E, low K+ increased the rate of entry into fast inactivation, hyperpolarized the g(V) and h(infinity) curves, and increased recovery delay. Biophysical underpinnings of PAM caused by mutations of G1306 thus vary with the specific mutation, and hyperkalemic exacerbation of effects of mutations at this residue are not direct.
authors.affiliation: Department of Biology, Idaho State University, Pocatello, ID, 83209-8007, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Groome
authors.forename: Esther
authors.initials: E
authors.lastname: Fujimoto
authors.forename: Peter C
authors.initials: PC
authors.lastname: Ruben
mesh_terms: D000818:Animals; D004553:Electric Conductivity; D006801:Humans; D015640:Ion Channel Gating; D007700:Kinetics; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D020125:Mutation, Missense / Q000235:genetics*; D009222:Myotonia / Q000235:genetics*; D062553:NAV1.4 Voltage-Gated Sodium Channel; D009865:Oocytes / Q000502:physiology; D015222:Sodium Channels / Q000378:metabolism*; D013997:Time Factors; D014981:Xenopus
chemical_list: D009124:Muscle Proteins; D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels