A mutation in segment I-S6 alters slow inactivation of sodium channels

Slow inactivation occurs in voltage-gated Na+ channels when the membrane is depolarized for several seconds, whereas fast inactivation takes place rapidly within a few milliseconds. Unlike fast inactivation, the molecular entity that governs the slow inactivation of Na+ channels has not been as well defined, Some regions of Na+ channels, such as mu 1-W402C and mu 1-T698M, have been reported to affect slow inactivation. A mutation in segment I-S6 of mu 1 Na+ channels, N434A, shifts the voltage dependence of activation and fast inactivation toward the depolarizing direction, The mutant Na+ current at +50 mV is diminished by 60-80% during repetitive stimulation at 5 Hz, resulting in a profound use-dependent phenomenon, This mutant phenotype is due to the enhancement of slow inactivation, which develops faster than that of wild-type channels (tau = 0.46 +/- 0.01 s versus 2.11 +/- 0.10 s at +30 mV, n = 9), An oxidant, chloramine-T, abolishes fast inactivation and yet greatly accelerates slow inactivation in both mutant and wild-type channels (tau = 0.21 +/-: 0.02 s and 0.67 +/- 0.05 s, respectively, n = 6), These findings together demonstrate that N434 of mu 1 Na+ channels is also critical for slow inactivation. We propose that this slow form of Na+ channel inactivation is analogous to the ''C-type'' inactivation in Shaker K+ channels.