DEFECTIVE FAST INACTIVATION RECOVERY AND DEACTIVATION ACCOUNT FOR SODIUM-CHANNEL MYOTONIA IN THE I1160V MUTANT

The skeletal muscle sodium channel mutant I1160V cosegregates with a d isease phenotype producing myotonic discharges (observed as muscle sti ffness) that are worsened by elevated K+ levels but unaffected by cool ing. The I1160V alpha-subunit was co-expressed with the beta 1-subunit in Xenopus oocytes. An electrophysiological characterization was unde rtaken to examine the underlying biophysical characteristics imposed b y this mutation. Two abnormalities were found. 1) The voltage dependen ce of steady-state fast inactivation was reduced in I1160V, which resu lted in faster rates of closed-state fast inactivation onset and recov ery in I1160V compared with wild-type channels. 2) The rates of deacti vation were slower in I1160V than in wild-type channels. Using a compu ter-simulated model, the combination of both defects elicited myotonic runs under conditions of elevated K+, consistent with the observed ph enotype of the mutant.