Role in fast inactivation of conserved amino acids in the IV/S4-S5 loop of the human muscle Na⁺ channel

Since it has been shown that point mutations in the S4-S5 loop of the Shaker K⁺ channel may disrupt fast inactivation, we investigated the role of three conserved amino acids in IV/S4-S5 of the adult human muscle Na⁺ channel (L1471, S1478, L1482). In contrast to the K⁺ channel mutations, the analogous substitutions in the Na⁺ channel (S1478A/C, L1482A) did not substantially affect fast inactivation. Nevertheless, the mutations S1478A/C/Q shifted the voltage dependence of steady-state inactivation; L1471Q and S1478C slowed recovery from inactivation. In contrast, a novel non-conserved IV/S4-S5 mutation causing paramyotonia congenita (F1473S) slowed fast inactivation 2-fold and accelerated recovery from inactivation 5-fold. The results indicate involvement of the IV/S4-S5 loop of the human muscle Na⁺ channel in fast inactivation, but different roles for conserved amino acids among Na⁺ and K⁺ channels.