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 mu1-W402C and mu1-T698M, have been reported to affect slow inactivation. A mutation in segment I-S6 of mu1 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 mu1 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.
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Department of Biological Sciences, State University of New York at Albany 12222, USA. wang@zeus.bwh.harvard.edu
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D000595:Amino Acid Sequence; D000818:Animals; D002700:Chloramines / Q000494:pharmacology; D004594:Electrophysiology; D015640:Ion Channel Gating; D007700:Kinetics; D008969:Molecular Sequence Data; D009132:Muscles; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D051637:Shaker Superfamily of Potassium Channels; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*; D014105:Tosyl Compounds / Q000494:pharmacology
D002700:Chloramines; D015221:Potassium Channels; D051637:Shaker Superfamily of Potassium Channels; D015222:Sodium Channels; D014105:Tosyl Compounds; C016300:chloramine-T