title: Biophysical characterization of M1476I, a sodium channel founder mutation associated with cold-induced myotonia in French Canadians.
abstract: M1476I, a French Canadian founder mutation of Na⁺ channel Nav1.4, causes potassium-aggravated myotonia, with cold-induced myotonia as the most distinctive clinical feature. Mexiletine, a class 1B local anaesthetic, relieves the myotonic symptoms of patients carrying the M1476I mutation. We used the patch-clamp method to investigate the functional characteristics of this mutation by heterologous expression in tsA201 cells. The M1476I mutation caused an increased persistent Na⁺ current, a 2- to 3-fold slower fast inactivation, a 6.4 mV depolarizing shift in the midpoint of steady-state inactivation, and an accelerated recovery from fast inactivation compared to the wild-type (WT) channel. Cooling slowed the kinetics of both channel types and increased the amplitude of the persistent current in M1476I channels.Mexiletine suppressed the persistent Na⁺ current generated by the M1476I mutation and blocked both WT and M1476I channels in a use- dependent manner. The inactivation-deficient M1476I channels were less susceptible to mexiletine during repetitive pulses. The decreased use-dependent block of M1476I channels might have resulted from the slower onset of mexiletine block, and/or the faster recovery from mexiletine block, given that the affinity of mexiletine for the inactivated state of the WT and mutant channels was similar. Increased extracellular concentrations of potassium had no effect on either M1476I or WT currents. These results indicated that cooling can augment the disruption of the voltage dependence of fast inactivation by M1476I channels.
authors.affiliation: Le Centre de recherche en neurosciences, Institut universitaire en santé mentale de Québec, 2601 Chemin de Canardière, Quebec, QC, G1J 2G3, Canada.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhao
authors.forename: Nicolas
authors.initials: N
authors.lastname: Duprè
authors.forename: Jack
authors.initials: J
authors.lastname: Puymirat
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chahine
mesh_terms: D002170:Canada; D002460:Cell Line; D003080:Cold Temperature; D006801:Humans; D008801:Mexiletine / Q000494:pharmacology; D009154:Mutation; D009222:Myotonia / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D011188:Potassium / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D061567:Voltage-Gated Sodium Channel Blockers / Q000494:pharmacology
chemical_list: D015222:Sodium Channels; D061567:Voltage-Gated Sodium Channel Blockers; D008801:Mexiletine; D011188:Potassium