Defective fast inactivation recovery and deactivation account for sodium channel myotonia in the I1160V mutant.

Abstract

The skeletal muscle sodium channel mutant I1160V cosegregates with a disease phenotype producing myotonic discharges (observed as muscle stiffness) that are worsened by elevated K+ levels but unaffected by cooling. The I1160V alpha-subunit was co-expressed with the beta1-subunit in Xenopus oocytes. An electrophysiological characterization was undertaken to examine the underlying biophysical characteristics imposed by this mutation. Two abnormalities were found. 1) The voltage dependence of steady-state fast inactivation was reduced in I1160V, which resulted in faster rates of closed-state fast inactivation onset and recovery in I1160V compared with wild-type channels. 2) The rates of deactivation were slower in I1160V than in wild-type channels. Using a computer-simulated model, the combination of both defects elicited myotonic runs under conditions of elevated K+, consistent with the observed phenotype of the mutant.

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@article{Richmond1997DefectiveFI, title={Defective fast inactivation recovery and deactivation account for sodium channel myotonia in the I1160V mutant.}, author={Jonathan E D Richmond and D VanDeCarr and David E Featherstone and Alfred L. George and Peter C Ruben}, journal={Biophysical journal}, year={1997}, volume={73 4}, pages={1896-903} }