Calcium-Activated K+ Channels (KCa) and Therapeutic Implications.
Calcium-Activated K+ Channels (KCa) and Therapeutic Implications.
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DOI：
10.1007/164_2021_459
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发表时间：
2021-01-01
影响因子：
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通讯作者：
Hollywood, Mark A
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文献类型：
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作者：
Dudem, Srikanth;Sergeant, Gerard P;Hollywood, Mark A
钾离子通道是细胞中发现的最多样和最普遍的离子通道家族。Ca2+门控和电压门控组成了一个亚家族，在可兴奋和非可兴奋细胞中发挥着多种作用，并根据其单通道电导进一步分为小电导（SK）、中电导（IK）和大电导（BK）K+通道。其功能在不同的组织中被不同的剪接变体以及包括β、γ和LINGO亚基的调节辅助亚基的扩展阵列修饰。我们将研究如何BK通道被修改这些监管亚基，并描述通道门控是如何改变电压和Ca2+，同时设置这与最近发表的BK通道的结构的背景下。最后，我们将讨论BK和其他钙激活通道是如何通过新型离子通道调节剂进行调节的，并描述与试图开发具有足够疗效、效力和选择性的化合物以获得治疗益处相关的一些挑战。
Potassium channels are the most diverse and ubiquitous family of ion channels found in cells. The Ca2+ and voltage gated members form a subfamily that play a variety of roles in both excitable and non-excitable cells and are further classified on the basis of their single channel conductance to form the small conductance (SK), intermediate conductance (IK) and big conductance (BK) K+ channels.In this chapter, we will focus on the mechanisms underlying the gating of BK channels, whose function is modified in different tissues by different splice variants as well as the expanding array of regulatory accessory subunits including beta, gamma and LINGO subunits. We will examine how BK channels are modified by these regulatory subunits and describe how the channel gating is altered by voltage and Ca2+ whilst setting this in context with the recently published structures of the BK channel. Finally, we will discuss how BK and other calcium-activated channels are modulated by novel ion channel modulators and describe some of the challenges associated with trying to develop compounds with sufficient efficacy, potency and selectivity to be of therapeutic benefit.