Mechanism of increased open probability by a mutation of the BK channel
Mechanism of increased open probability by a mutation of the BK channel
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DOI：
10.1152/jn.00461.2006
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发表时间：
2006-09-01
影响因子：
2.5
通讯作者：
Richerson, George B.
中科院分区：
文献类型：
--
作者：
Diez-Sampedro, Ana;Silverman, William R.;Richerson, George B.
最近在人大电导钙激活钾（BK）通道α亚基中发现了一个错义突变（D434 G）。有趣的是，虽然突变导致开放概率增加，但携带突变的个体患有癫痫和/或阵发性运动障碍，这是一种大脑兴奋性增加的疾病。为了定义突变的机制，我们使用了从单通道的记录和宏观电导的测量来检查α亚基的门控，调节β 4亚基的调制，以及Mg 2+对通道特性的影响。尽管突变体和野生型α亚基的开放停留时间差异相对较小，但突变体通道在长寿命封闭状态下花费的时间更少。β 4亚基的共表达导致野生型通道在低Ca 2+浓度下对钙不太敏感，但对突变型通道几乎没有影响，进一步加剧了野生型和突变型通道之间的差异。在Ca 2+的情况下，突变体和野生型通道的Mg 2+或电压敏感性没有差异，而在2 mM Ca 2+中，突变体通道在每个Mg 2+浓度下都有更大的开放概率。我们的结论是，D434 G突变修改钙离子依赖的激活，但我们没有发现直接影响激活镁离子或电压的证据。BK通道功能的增强导致大脑兴奋性的增加，可能是由于动作电位的更快复极。
A missense mutation (D434G) has recently been identified in the alpha subunit of the human large-conductance calcium-activated potassium (BK) channel. Interestingly, although the mutation causes an increase in open probability, individuals that carry the mutation have epilepsy and/or paroxysmal dyskinesia, disorders of increased brain excitability. To define the mechanisms of the mutation, we have used recordings from single channels and measurement of macroscopic conductances to examine the gating of the alpha subunit, modulation by the regulatory beta 4 subunit, and the effect of Mg2+ on channel properties. Although there was relatively little difference in open dwell times for the mutant and wild-type alpha subunits, the mutant channel spent less time in a long-lived closed state. Co-expression of the beta 4 subunit caused the wildtype channel to be less sensitive to calcium at low Ca2+ concentrations but had little effect on the mutant channel, further accentuating the difference between the wild-type and the mutant channels. In the absence of Ca2+, there was no difference in Mg2+ or voltage sensitivity of the mutant and wild-type channels, whereas in 2 mM Ca2+, the mutant channel had greater open probability at every Mg2+ concentration tested. We conclude that the D434G mutation modifies Ca2+-dependent activation, but we find no evidence of a direct effect on activation by Mg2+ or voltage. The resulting enhancement of BK channel function leads to an increase in brain excitability, possibly due to more rapid repolarization of action potentials.