β subunit-specific modulations of BK channel function by a mutation associated with epilepsy and dyskinesia
β subunit-specific modulations of BK channel function by a mutation associated with epilepsy and dyskinesia
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DOI：
10.1113/jphysiol.2009.169243
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发表时间：
2009-04-01
影响因子：
5.5
通讯作者：
Cui, Jianmin
中科院分区：
文献类型：
--
作者：
Lee, Urvi S.;Cui, Jianmin
大电导Ca ~（2+）激活的K ~+（BK）通道调节神经元兴奋性、突触传递和肌源性紧张性等多种生理过程。最近发现BK通道的成孔α亚基（Slo 1）中的功能获得性（E/D）突变，并与共存的全身性癫痫和阵发性运动障碍的人类神经系统疾病有关。在这里，我们进行了宏观电流记录，以检查E/D突变对门控动力学的影响，以及在四种不同的β亚基（β 1-4）存在下BK通道激活的电压和Ca 2+依赖性。这些β亚基以组织特异性模式表达，并以不同方式调节BK通道功能，为各种生理过程中的BK通道提供多样性和特异性。我们的研究结果表明，在人类（h）Slo 1-only通道中，E/D突变增加了开放速率并降低了关闭速率，允许更多数量的通道在更负的电位下打开，无论是在存在还是不存在Ca 2+的情况下，由于与野生型通道相比，Ca 2+亲和力增加和激活增强。即使在β亚基的存在下，E/D突变也表现出这些变化，但β 3b除外，其中Ca 2+敏感性变化不大。然而，这些变化的定量检测显示了每个β亚基的多样性和E/D突变对这些亚基的差异调节。例如，在β 1亚基的存在下，E/D突变增加的Ca 2+敏感性较小，但在不存在Ca 2+的情况下比在仅hSlo 1通道中增强的通道激活更多，而在β 2亚基的存在下，E/D突变也改变了失活特性。这些发现表明，根据大脑中各种β亚基的分布，E/D突变可以不同地调节BK通道，从而促进癫痫和运动障碍的病理生理学。此外，这些结果还对BK通道发挥重要作用的脑以外组织的生理过程具有影响。
Large conductance Ca2+-activated K+ (BK) channels modulate many physiological processes including neuronal excitability, synaptic transmission and regulation of myogenic tone. A gain-of-function (E/D) mutation in the pore-forming alpha subunit (Slo1) of the BK channel was recently identified and is linked to human neurological diseases of coexistent generalized epilepsy and paroxysmal dyskinesia. Here we performed macroscopic current recordings to examine the effects of the E/D mutation on the gating kinetics, and voltage and Ca2+ dependence of the BK channel activation in the presence of four different beta subunits (beta 1-4). These beta subunits are expressed in a tissue-specific pattern and modulate BK channel function differently, providing diversity and specificity for BK channels in various physiological processes. Our results show that in human (h) Slo1-only channels, the E/D mutation increased the rate of opening and decreased the rate of closing, allowing a greater number of channels to open at more negative potentials both in the presence and absence of Ca2+ due to increased Ca2+ affinity and enhanced activation compared with the wild-type channels. Even in the presence of beta subunits, the E/D mutation exhibited these changes with the exception of beta 3b, where Ca2+ sensitivity changed little. However, quantitative examination of these changes shows the diversity of each beta subunit and the differential modulation of these subunits by the E/D mutation. For example, in the presence of the beta 1 subunit the E/D mutation increased Ca2+ sensitivity less but enhanced channel activation in the absence of Ca2+ more than in hSlo1-only channels, while in the presence of the beta 2 subunit the E/D mutation also altered inactivation properties. These findings suggest that depending on the distribution of the various beta subunits in the brain, the E/D mutation can modulate BK channels differently to contribute to the pathophysiology of epilepsy and dyskinesia. Additionally, these results also have implications on physiological processes in tissues other than the brain where BK channels play an important role.