Inactivation gating of Kv4 potassium channels: molecular interactions involving the inner vestibule of the pore.
Inactivation gating of Kv4 potassium channels: molecular interactions involving the inner vestibule of the pore.
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DOI：
10.1085/jgp.113.5.641
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发表时间：
1999-05
期刊：
影响因子：
--
通讯作者：
Covarrubias M
中科院分区：
文献类型：
--
作者：
Jerng HH;Shahidullah M;Covarrubias M
Kv4 通道代表大脑 A 型 K+ 通道的主要类别，在膜电位阈下范围内工作（Serodio, P., E. Vega-Saenz de Miera, 和 B. Rudy. 1996. J. Neurophysiol. 75:2174–2179），其功能主要取决于失活门控。先前的研究表明，Kv4.1 通道的细胞质 NH2 和 COOH 末端结构域协同作用，决定了宏观失活的复杂时间过程的快相（Jerng, H.H., and M. Covarrubias. 1997. Biophys. J. 72:163–174）。为了研究这些通道缓慢失活门控的结构基础，我们检查了可能影响 4-氨基吡啶 (4-AP) 失活和封闭状态阻断之间相互排斥关系的内部残基 (Campbell, D.L., Y. Qu, R.L. Rasmussen, and H.C. Strauss. 1993. J. Gen. Physiol. 101:603–626; Shieh, C.-C. 和 G.E.Kirsch，1994 年。《生物物理学》，67：2316-2325。该蛋白 S6 区远端部分的双突变 V[404,406]I 大大减缓了通道失活和失活，并显着减少了 4-AP 的阻断。此外，失活恢复速度稍快，但孔隙特性并未受到显着影响。与更稳定的开放态和破坏的闭合态失活一致，V[404,406]I还分别引起峰值电导电压曲线（~5 mV）和预脉冲失活曲线（>10 mV）的超极化和去极化偏移。相比之下，经历 N 型和 C 型失活 (Kv1.4) 的 K+ 通道中的类似突变 (V[556,558]I) 不会影响宏观失活，但会显着减慢失活和失活恢复，并消除 4-AP 的开放通道阻断。 Kv4.1 的 S4-S5 环 (C322S) 中 Kv4 特异性残基的突变也改变了门控和 4-AP 敏感性，其方式与 V[404,406]I 的影响非常相似。然而，该突变体并未表现出破坏的封闭状态失活。假设去极化膜电位下通道关闭和失活之间存在耦合的动力学模型解释了这些结果。我们认为孔内部前庭的成分控制 Kv4 K+ 通道的关闭和失活。
Kv4 channels represent the main class of brain A-type K+ channels that operate in the subthreshold range of membrane potentials (Serodio, P., E. Vega-Saenz de Miera, and B. Rudy. 1996. J. Neurophysiol. 75:2174– 2179), and their function depends critically on inactivation gating. A previous study suggested that the cytoplasmic NH2- and COOH-terminal domains of Kv4.1 channels act in concert to determine the fast phase of the complex time course of macroscopic inactivation (Jerng, H.H., and M. Covarrubias. 1997. Biophys. J. 72:163–174). To investigate the structural basis of slow inactivation gating of these channels, we examined internal residues that may affect the mutually exclusive relationship between inactivation and closed-state blockade by 4-aminopyridine (4-AP) (Campbell, D.L., Y. Qu, R.L. Rasmussen, and H.C. Strauss. 1993. J. Gen. Physiol. 101:603–626; Shieh, C.-C., and G.E. Kirsch. 1994. Biophys. J. 67:2316–2325). A double mutation V[404,406]I in the distal section of the S6 region of the protein drastically slowed channel inactivation and deactivation, and significantly reduced the blockade by 4-AP. In addition, recovery from inactivation was slightly faster, but the pore properties were not significantly affected. Consistent with a more stable open state and disrupted closed state inactivation, V[404,406]I also caused hyperpolarizing and depolarizing shifts of the peak conductance–voltage curve (∼5 mV) and the prepulse inactivation curve (>10 mV), respectively. By contrast, the analogous mutations (V[556,558]I) in a K+ channel that undergoes N- and C-type inactivation (Kv1.4) did not affect macroscopic inactivation but dramatically slowed deactivation and recovery from inactivation, and eliminated open-channel blockade by 4-AP. Mutation of a Kv4-specifc residue in the S4–S5 loop (C322S) of Kv4.1 also altered gating and 4-AP sensitivity in a manner that closely resembles the effects of V[404,406]I. However, this mutant did not exhibit disrupted closed state inactivation. A kinetic model that assumes coupling between channel closing and inactivation at depolarized membrane potentials accounts for the results. We propose that components of the pore's internal vestibule control both closing and inactivation in Kv4 K+ channels.
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影响因子：
56.9
作者：
Doyle, DA;Cabral, JM;MacKinnon, R
通讯作者：
MacKinnon, R
影响因子：
16.2
作者：
KIRSCH, GE;SHIEH, CC;BROWN, AM
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3
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20.1
作者：
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3.8
作者：
CAMPBELL, DL;QU, YH;STRAUSS, HC
通讯作者：
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