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J Bioenerg Biomembr
1999 Dec 01;316:591-608. doi: 10.1023/a:1005473129183.
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Myopathic mutations affect differently the inactivation of the two gating modes of sodium channels.
Moran O, Nizzari M, Conti F.
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Three groups of mutations of the alpha subunit of the rat skeletal muscle sodium channel (rSkM1), homologous to mutations linked to human muscle hereditary diseases, have been studied by heterologous expression in frog oocytes: S798F, G1299E, G1299V, and G1299A, linked with potassium-aggravated myotonia (PAM); T1306M, R1441C and R1441P, linked with paramyotonia 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 differ mainly in the process of inactivation. The naturally most representative mode M1 is tenfold faster and develops at approximately 30 mV less depolarized potentials. A common feature of myopathy-linked mutants is an increase in the mode M2 probability, P(M2), but phenotype-specific alterations of voltage-dependence and kinetics of inactivation of both modes are also observed. The coexpression of the sodium channel beta1 subunit, which has been studied for WT and for the five best expressing mutants, generally caused a threefold reduction of P(M2) without changing the properties of the individual modes. This indicates that the mutations do not affect the alpha - beta1 interaction and that the phenotypic changes in P(M2) observed for the enhanced mode M2 behavior of the sole alpha subunits, although largely depressed in the native tissue, are likely to be the most important functional modification that causes the muscle hyperexcitability observed in all patients carrying the myotonic mutations. The interpretation of the more phenotype-specific changes revealed by our study is not obvious, but it may offer clues for understanding the different clinical manifestations of the diseases associated with the various mutations.
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