A mutation in segment I-S6 alters slow inactivation of sodium channels
A mutation in segment I-S6 alters slow inactivation of sodium channels
复制标题
DOI：
10.1016/s0006-3495(97)78809-x
复制
发表时间：
1997-04-01
影响因子：
3.4
通讯作者：
Wang, GK
中科院分区：
文献类型：
--
作者：
Wang, SY;Wang, GK
当膜去极化几秒钟时，电压门控Na+通道发生缓慢失活，而快速失活在几毫秒内迅速发生。与快速失活不同，控制Na+通道缓慢失活的分子实体尚未得到很好的定义。Na+通道的一些区域，如mu 1-W 402 C和mu 1-T698 M，已被报道影响缓慢失活。mu_1钠离子通道I-S6段N434 A突变使钠离子通道的激活和快速失活的电压依赖性向去极化方向移动。在5 Hz重复刺激时，+50mV的突变钠离子通道电流减少60-80%，导致严重的使用依赖性现象。这种突变表型是由于慢失活增强所致。比野生型通道发育得更快（tau = 0.46 +/- 0.01 s vs 2.11 +/- 0.10 s，+30 mV，n = 9），氧化剂氯胺-T消除了突变型和野生型通道的快速失活，但大大加速了缓慢失活（tau = 0.21 +/-：分别为0.02 s和0.67 +/- 0.05 s，n = 6）。这些发现共同表明，mu 1 Na+通道的N434对于缓慢失活也是关键的。我们认为这种缓慢形式的Na+通道失活类似于Shaker K+通道中的“C型”失活。
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.