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BKCa通道外孔中负电荷环对钾离子流的调节。第二部分:天冬氨酸292的中和作用会减少通道的长时间开放和门控电流慢成分。

Regulation of K+ flow by a ring of negative charges in the outer pore of BKCa channels. Part II: Neutralization of aspartate 292 reduces long channel openings and gating current slow component.

作者信息

Haug Trude, Olcese Riccardo, Toro Ligia, Stefani Enrico

机构信息

Department of Anesthesiology, Division of Molecular Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095-7115, USA.

出版信息

J Gen Physiol. 2004 Aug;124(2):185-97. doi: 10.1085/jgp.200308950.

Abstract

Neutralization of the aspartate near the selectivity filter in the GYGD pore sequence (D292N) of the voltage- and Ca(2+)-activated K+ channel (MaxiK, BKCa) does not prevent conduction like the corresponding mutation in Shaker channel, but profoundly affects major biophysical properties of the channel (Haug, T., D. Sigg, S. Ciani, L. Toro, E. Stefani, and R. Olcese. 2004. J. Gen. Physiol. 124:173-184). Upon depolarizations, the D292N mutant elicited mostly gating current, followed by small or no ionic current, at voltages where the wild-type hSlo channel displayed robust ionic current. In fact, while the voltage dependence of the gating current was not significantly affected by the mutation, the overall activation curve was shifted by approximately 20 mV toward more depolarized potentials. Several lines of evidence suggest that the mutation prevents population of certain open states that in the wild type lead to high open probability. The activation curves of WT and D292N can both be fitted to the sum of two Boltzmann distributions with identical slope factors and half activation potentials, just by changing their relative amplitudes. The steeper and more negative component of the activation curve was drastically reduced by the D292N mutation (from 0.65 to 0.30), suggesting that the population of open states that occurs early in the activation pathway is reduced. Furthermore, the slow component of the gating current, which has been suggested to reflect transitions from closed to open states, was greatly reduced in D292N channels. The D292N mutation also affected the limiting open probability: at 0 mV, the limiting open probability dropped from approximately 0.5 for the wild-type channel to 0.06 in D292N (in 1 mM [Ca2+]i). In addition to these effects on gating charge and open probability, as already described in Part I, the D292N mutation introduces a approximately 40% reduction of outward single channel conductance, as well as a strong outward rectification.

摘要

在电压和Ca(2+)激活的钾通道(大电导钙激活钾通道,MaxiK,BKCa)的GYGD孔道序列(D292N)中,选择性过滤器附近的天冬氨酸被中和,这不像在Shaker通道中的相应突变那样阻止离子传导,但却深刻影响通道的主要生物物理特性(豪格,T.,D.西格,S.恰尼,L.托罗,E.斯特凡尼,以及R.奥尔切塞。2004年。《普通生理学杂志》124:173 - 184)。去极化时,在野生型hSlo通道显示出强大离子电流的电压下,D292N突变体主要引发门控电流,随后是小的离子电流或无离子电流。实际上,虽然门控电流的电压依赖性没有受到突变的显著影响,但总体激活曲线向更去极化的电位方向移动了约20 mV。几条证据表明,该突变阻止了某些开放状态的出现,而在野生型中这些开放状态会导致高开放概率。野生型和D292N的激活曲线都可以通过改变它们的相对幅度,拟合为两个具有相同斜率因子和半激活电位的玻尔兹曼分布的总和。D292N突变极大地降低了激活曲线更陡峭且更负的成分(从0.65降至0.30),这表明在激活途径早期出现的开放状态的数量减少了。此外,门控电流的慢成分被认为反映了从关闭状态到开放状态的转变,在D292N通道中大大减少。D292N突变还影响了极限开放概率:在0 mV时,极限开放概率从野生型通道的约0.5降至D292N中的0.06(在1 mM [Ca2+]i中)。除了对门控电荷和开放概率的这些影响外,如第一部分中已经描述的,D292N突变使外向单通道电导降低了约40%,并且产生了强烈的外向整流。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/92a9/2229619/1b4307c77916/200308950f2.jpg

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