NDLI: Biophysical characterization of M1476I, a sodium channel founder mutation associated with cold-induced myotonia in French Canadians

Content Provider	PubMed Central
Author	Zhao, Juan Nicolas, Duprè Jack, Puymirat Chahine, Mohamed
Copyright Year	2012
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. The therapeutic efficacy of mexiletine in M1476I carriers may be partly due to the open-channel block targeting the persistent Na+ currents generated by M1476I channels.
Related Links	http://dx.doi.org/10.1113/jphysiol.2011.223461
Ending Page	2644
Page Count	16
Starting Page	2629
File Format	PDF
ISSN	00223751
e-ISSN	14697793
Journal	The Journal of Physiology
Issue Number	Pt 11
Volume Number	590
Language	English
Publisher	Blackwell Science Inc
Publisher Date	2012-06-01
Access Restriction	Open
Rights Holder	Blackwell Science Inc
Subject Keyword	Physiology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Physiology Sports Science

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