Inactivation defects produced by a myopathic II-S6 mutation of the muscle sodium channel.

We have studied the expression in frog oocytes of the alpha-subunit of the rat skeletal muscle sodium channel mutation S798F, homologous to the mutation S804F of the human isoform, that causes potassium aggravated myotony (PAM), a muscular hereditary disease in humans. Wild type channels show a bimodal inactivation, with two gating modes that inactivate with time constants that differ at least by one order of magnitude and a steady steady-state voltage dependence of the slow mode shifted by +27 mV relative to that of the fast mode. In the myopathy-linked mutant the propensity of the channel to gate in the slow mode is significantly increased and there are alterations in the inactivation properties of both modes. The half inactivation potential of the fast mode is shifted negatively, and the inactivation kinetics of both modes are slower, with an apparent shift in their voltage dependence. The changes on the inactivation properties of the mutant channel may be related with the muscle fibre hyperexcitability observed patients affected by PAM.