Abstract:
Large-conductance Ca2+- and voltage-activated K+ (BK) channels play many physiological roles ranging from the maintenance of smooth muscle tone to hearing and neurosecretion. BK channels are tetramers in which the pore-forming α subunit is coded by a single gene (Slowpoke, KCNMA1). In this review, we first highlight the physiological importance of this ubiquitous channel, emphasizing the role that BK channels play in different channelopathies. We next discuss the modular nature of BK channel-forming protein, in which the different modules (the voltage sensor and the Ca2+ binding sites) communicate with the pore gates allosterically. In this regard, we review in detail the allosteric models proposed to explain channel activation and how the models are related to channel structure. Considering their extremely large conductance and unique selectivity to K+, we also offer an account of how these two apparently paradoxical characteristics can be understood consistently in unison, and what we have learned about the conduction system and the activation gates using ions, blockers, and toxins. Attention is paid here to the molecular nature of the voltage sensor and the Ca2+ binding sites that are located in a gating ring of known crystal structure and constituted by four COOH termini. Despite the fact that BK channels are coded by a single gene, diversity is obtained by means of alternative splicing and modulatory β and γ subunits. We finish this review by describing how the association of the α subunit with β or with γ subunits can change the BK channel phenotype and pharmacology.
摘要:
大电导Ca2-和电压激活的K(BK)通道起着许多生理作用,从维持平滑肌张力到听力和神经分泌。BK通道是四聚体,其中成孔的α亚基由单个基因编码(Slowpoke,KCNMA1)。在这次审查中,我们首先强调这个无处不在的通道的生理重要性,强调BK频道在不同频道中的作用。我们接下来讨论BK通道形成蛋白的模块性质,其中不同的模块(电压传感器和Ca2+结合位点)与孔门变构连通。在这方面,我们详细回顾了为解释通道激活而提出的变构模型,以及这些模型如何与通道结构相关。考虑到它们极大的电导和对K+的独特选择性,我们还介绍了如何一致地理解这两个看似矛盾的特征,我们所了解的传导系统和使用离子的激活门,阻滞剂,和毒素。这里要注意电压传感器的分子性质和Ca2结合位点,它们位于已知晶体结构的门控环中并由四个COOH末端构成。尽管BK通道由单个基因编码,多样性是通过选择性剪接和调节β和γ亚基获得的。我们通过描述α亚基与β或γ亚基的关联如何改变BK通道表型和药理学来完成这篇综述。