Myopathic Mutations Affect Differently the Inactivation of the Two Gating Modes of Sodium Channels

Three groups of mutations of the subunit of the rat skeletal muscle sodium channel (rSkM1),homologous to mutations linked to human muscle hereditary diseases, have been studied byheterologous expression in frog oocytes: S798F, G1299E, G1299V, and G1299A, linked withpotassium-aggravated myotonia (PAM); T1306M, R1441C and R1441P, linked withparamyotonia congenita (PC); T698M and M1353V, linked with the hyperkalemic periodic paralysis(HyPP). Wild-type rSkM1 channels (WT) show two gating modes, M1 and M2, which differmainly in the process of inactivation. The naturally most representative mode M1 is tenfoldfaster and develops at 30 mV less depolarized potentials. A common feature ofmyopathy-linked mutants is an increase in the mode M2 probability, P_M2, but phenotype-specific alterationsof voltage-dependence and kinetics of inactivation of both modes are also observed. Thecoexpression of the sodium channel ₁ subunit, which has been studied for WT and for thefive best expressing mutants, generally caused a threefold reduction of P_M2 without changingthe properties of the individual modes. This indicates that the mutations do not affect the – ₁ interaction and that the phenotypic changes in P_M2 observed for the enhanced mode M2behavior of the sole subunits, although largely depressed in the native tissue, are likely to bethe most important functional modification that causes the muscle hyperexcitability observed inall patients carrying the myotonic mutations. The interpretation of the more phenotype-specificchanges revealed by our study is not obvious, but it may offer clues for understanding the differentclinical manifestations of the diseases associated with the various mutations.