SLO family potassium channels: function and physiology

SLO 家族钾通道：功能和生理学

• 批准号: 10592285
• 负责人: Christopher J Lingle
• 金额: $ 71.15万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592285
• 关键词: Action Potentials; Address; Animal Model; Behavior; Binding Sites; Biophysics; Calcium; Cell physiology; Cells; Colon; Coupled; Electrophysiology (science); Epilepsy; Epithelial Cells; Epithelium; Evaluation; Family; Family member; Feedback; Future; Genes; Genetic; Homologous Gene; Hypertension; Inner Hair Cells; Ion Channel; Ions; Knock-out; Laboratories; Link; Methods; Modeling; Mus; Pathologic; Pathology; Physiological; Physiology; Play; Potassium Channel; Property; Regulation; Role; Stroke; Tissues; Work; animal model development; biophysical analysis; fascinate; genetic manipulation; insight; large-conductance calcium-activated potassium channels; stoichiometry; therapeutic target; tumor growth; voltage

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.

摘要 BK（或SLO 1）型钾通道是一种广泛表达的离子通道，它通过钙离子和电压调节，影响钾通道的功能。 调节各种可兴奋和不可兴奋组织的兴奋性。SLO 1由 kcnma 1（或slo 1）基因是SLO家族的四个成员之一。SLO系列通道的调节能力， 特异性胞质离子来自含有特异性离子结合位点的大的胞质调节结构域， 连接到亚单元的成孔部分。SLO家族渠道应对变化的能力 使它们独特地适应于在活性后发挥负反馈作用， 导致细胞溶质离子的改变。钙调节的BK通道特别迷人，因为尽管 由于它是由一个单一的基因编码，它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。 生理作用。该实验室工作的一个中心原则是， BK通道所起的相关广泛的生理作用来自于与调节 亚单位。对于BK通道，多达四种不同的调节性β亚基（β 1-β 4）和β 2-β 3-β 4-β-4- 四个BK亚基可以定义BK功能和生理学。我们对表达的位点， 特定细胞中的组成，以及特定调节亚基对功能和生理的影响 仍然是基本的。β-淀粉样蛋白和β-淀粉样蛋白4亚基分别与高血压和癫痫有关， 其他迹象表明，BK通道可能是中风、高血压、癫痫和 肿瘤生长调节为了解决在理解特定亚基的BK通道的作用方面的差距， 该实验室结合了从通道特性的生物物理分析到使用 特定调节亚基的基因敲除（KO）。这不仅允许评估生物物理和 在天然细胞中不同辅助亚基组成的通道的功能特性，而且这些 通道有助于生理作用。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有关，由可用的结构信息指导。 本实验室开发的动物模型的最新工作已经确定了BMP 1和BMP 2亚基在以下方面的重要作用： 分别在分泌上皮细胞和内毛细胞中定义BK通道功能，而含有BK 2的 BK通道影响动作电位放电率和爆发行为。未来的工作将进一步探讨我们的 现有的模型，例如，结肠上皮中含BK 1的BK通道的作用。此外，一个主要的重点将是 开发动物模型，以检查天然细胞中含有BK 3的BK电流。 含BK 3的BK通道仍然是所有BK通道亚基中了解最少的，我们试图补救这一点。 赤字该项目有望为研究β_3和β_1辅助蛋白的生理作用提供新的视角。 亚基，以及含有这些亚基的BK通道的作用。