An inactivation gate in the selectivity filter of KCNQ1 potassium channels
An inactivation gate in the selectivity filter of KCNQ1 potassium channels
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DOI：
10.1529/biophysj.107.107987
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发表时间：
2007-12-15
影响因子：
3.4
通讯作者：
Attali, Bernard
中科院分区：
文献类型：
--
作者：
Gibor, Gilad;Yakubovich, Daniel;Attali, Bernard
失活是大多数电压门控K+通道的固有特性。虽然快速N-型失活已经在生物物理和结构细节分析，慢失活的机制还知之甚少。在这里，我们的特点是在各种KCNQ 1孔突变体，包括L273 F，这阻碍了外部Ba 2+进入其在孔的深层网站，并通过减缓其出口陷阱的缓慢失活机制。动力学研究，分子建模和动力学模拟表明，这种缓慢的失活涉及构象变化，收敛到外羰基环的选择性过滤器，其中的骨干变得不那么灵活。这一机制涉及加速失活动力学和增强Ba 2+捕获在升高的外部K+浓度。因此，KCNQ 1慢失活与C型失活有很大不同，C型失活引起K+从滤器中的释放。我们认为，由于过滤器的刚性和脱水-溶解转变的阻碍，K+在s（1）处的捕获是KCNQ 1孔突变体缓慢失活的基础。
Inactivation is an inherent property of most voltage-gated K+ channels. While fast N-type inactivation has been analyzed in biophysical and structural details, the mechanisms underlying slow inactivation are yet poorly understood. Here, we characterized a slow inactivation mechanism in various KCNQ1 pore mutants, including L273F, which hinders entry of external Ba2+ to its deep site in the pore and traps it by slowing its egress. Kinetic studies, molecular modeling, and dynamics simulations suggest that this slow inactivation involves conformational changes that converge to the outer carbonyl ring of the selectivity filter, where the backbone becomes less flexible. This mechanism involves acceleration of inactivation kinetics and enhancement of Ba2+ trapping at elevated external K+ concentrations. Hence, KCNQ1 slow inactivation considerably differs from C-type inactivation where vacation of K+ from the filter was invoked. We suggest that trapping of K+ at s(1) due to filter rigidity and hindrance of the dehydration-resolvation transition underlie the slow inactivation of KCNQ1 pore mutants.