A mutation that causes ataxia shifts the voltage-dependence of the Scn8a sodium channel

A mutation of alanine to threonine in the III S4-S5 linker of the mouse Scn 8a sodium channel has previously been identified as causing the ataxia in m ed(jo) mice. The electrophysiological effects of this mutation in Scn8a sod ium channels were characterized in Xenopus oocytes. The med(jo) mutation ca used a 10 mV positive shift in the voltage dependence of activation, withou t any significant changes in the kinetics of either inactivation or recover y from inactivation. The shift in the voltage-dependence of activation obse rved for the mutant channel would reduce the spontaneous activity of Purkin je cells and lead to a decrease in output from the cerebellum, which is con sistent with the phenotype of cerebellar ataxia observed in med(jo) mice. ( C) 1999 Lippincott Williams & Wilkins.