A critical role for the S4-S5 intracellular loop in domain IV of the sodium channel alpha-subunit in fast inactivation.

The Journal of Biological Chemistry
J C McPheeW A Catterall

Abstract

Na+ channel fast inactivation is thought to involve the closure of an intracellular inactivation gate over the channel pore. Previous studies have implicated the intracellular loop connecting domains III and IV and a critical IFM motif within it as the inactivation gate, but amino acid residues at the intracellular mouth of the pore required for gate closure and binding have not been positively identified. The short intracellular loops connecting the S4 and S5 segments in each domain of the Na+ channel alpha-subunit are good candidates for this role in the Na+ channel inactivation process. In this study, we used scanning mutagenesis to examine the role of the IVS4-S5 region in fast inactivation. Mutations F1651A, near the middle of the loop, and L1660A and N1662A, near the COOH-terminal end, substantially disrupted Na+ channel fast inactivation. The mutant F1651A conducted Na+ currents that decayed very slowly, while L1660A and N1662A had large sustained Na+ currents at the end of 30-ms depolarizing pulses. Inactivation of macroscopic Na+ currents was nearly abolished by the N1662A mutation and the combination of the F1651A/L1660A mutations. Single channel analysis revealed frequent reopenings for all three mutants during 40-ms...Continue Reading

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