SLO family potassium channels: function and physiology

摘要 钙离子和电压调节的BK(或SLO1)型K+通道是一种广泛表达的离子通道 关于各种可兴奋和不可兴奋组织中兴奋性的调节。SLO1由 Kcnma1(或SLO1)基因，SLO家族四个成员之一。SLO家族渠道受监管的能力 特定的胞浆离子来自一个大的胞浆调节域，包含特定的离子结合部位， 连接到亚基的孔道形成部分。SLO家族渠道应对变化的能力 在胞液环境中使它们独特地适应在以下活动之后扮演负反馈角色 导致胞液离子的变化。钙调节的BK通道特别吸引人，因为尽管 它由单个基因编码，在各种各样的细胞中表达，在每种情况下都发挥着非常不同的作用 生理角色。该实验室工作的一个中心原则是，功能多样性和 与BK通道相关的广泛的生理作用源于与调节相关的 亚单位。对于BK通道，组织特异性表达多达四个不同的调节亚单位(1-4)和 四个亚基可以决定BK的功能和生理。我们对表达轨迹、渠道的理解 特定细胞的组成，以及特定调节亚基对功能和生理的影响 仍处于初级阶段。和4亚基分别与高血压和癫痫有关，以及 其他迹象表明，BK通道可能是中风、高血压、癫痫和 肿瘤生长调控。为了解决对特定亚基BK通道作用的理解上的差距 组成，这个实验室结合了从对通道属性的生物物理分析到使用 特定调控亚基的基因敲除(KO)。这不仅允许评估生物物理和 天然细胞中不同辅助亚基组成的通道的功能特性，以及这些通道是如何 通道对生理作用有贡献。此外，我们继续探讨BK通道功能的问题 与通道失活机制和化学计量学有关，由现有的结构信息指导。 最近在本实验室建立的动物模型上的工作已经确定了1和2亚单位在 分别在分泌上皮细胞和内毛细胞中确定BK通道功能，同时含有 BK通道影响动作电位、放电频率和突发行为。未来的工作将进一步探索我们的 现有的模型，例如，含有1的BK通道在结肠上皮中的作用。此外，一个主要焦点将是 是动物模型的发展，将允许检查天然细胞中含有3的BK电流。 包含3的BK通道仍然是所有BK通道亚基中最不被了解的，我们试图纠正这一点 赤字。该项目有望对3和1辅助蛋白的生理作用提供新的见解 亚基，以及包含这些亚基的BK通道的作用。

Abstract The calcium and voltage regulated BK(or SLO1)-type K+ channel is a widely expressed ion channel impacting on regulation of excitability in a variety of both excitable and inexcitable tissues. SLO1 is encoded by the kcnma1(or slo1) gene, one of four SLO family members. The ability of SLO family channels to be regulated by specific cytosolic ions arises from a large cytosolic regulatory domain, containing specific ion binding sites, that is connected to the pore-forming part of the subunits. The ability of SLO family channels to respond to changes in the cytosolic milieu makes them uniquely adapted to play negative feedback roles following activity that leads to alterations in the cytosolic ions. The Ca-regulated BK channel is particularly fascinating, since despite being encoded by a single gene, it is expressed in a wide variety of cells in each case playing very distinct physiological roles. A central tenet of the work in this laboratory is that the functional diversity and the associated broad scope of physiological roles played by BK channels arises from associated with regulatory subunits. For BK channels, tissue-specific expression of up to four different regulatory  subunits (1-4) and four  subunits can define BK function and physiology. Our understanding of the loci of expression, channel composition in particular cells, and the impact of particular regulatory subunits on function and physiology remains rudimentary. and 4 subunits have been implicated in hypertension and epilepsy, respectively, and other indications suggest that BK channels may be therapeutic targets in stroke, hypertension, epilepsy, and tumor growth regulation. To address the gaps in understanding of the roles of BK channels of particular subunit composition, this lab combines methods ranging from biophysical analysis of channel properties to the use of genetic knock-out (KO) of specific regulatory subunits. This permits evaluation not only of the biophysical and functional properties of channels of different auxiliary subunit composition in native cells, but also how these channels contribute to physiological roles. Furthermore, we continue to probe questions of BK channel function pertinent to channel inactivation mechanisms and stoichiometry, guided by available structural information. Recent work on animal models developed in this lab have established important roles of 1 and 2 subunits in defining BK channel functions in secretory epithelial cells and inner hair cells, respectively, while -containing BK channels influence action potential firing rates and burst behavior. Future work will further probe our existing models, e.g., the role of 1-containing BK channels in colonic epithelium. In addition, a major focus will be the development of animal models that will allow examination of 3-containing BK currents in native cells. 3-containing BK channels remain the least understood of all BK channel subunits and we seek to remedy that deficit. This project is expected to provide new insight into the physiological roles of 3 and 1 auxiliary subunits, and the roles of BK channels containing such subunits.