SLO family potassium channels: function and physiology

SLO 家族钾通道：功能和生理学

• 批准号: 9895824
• 负责人: Christopher J Lingle
• 金额: $ 65.61万
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895824
• 关键词: Animals; Behavioral; Binding Sites; Biophysics; Calcium; Cell physiology; Cells; Coupled; Disease; Electrophysiology (science); Epilepsy; Family; Family member; Feedback; Future; Genes; Genetic; Homologous Gene; Hypertension; Ion Channel; Ions; Knock-out; Knockout Mice; Ligands; Link; Location; Mediating; Methods; Modeling; Mus; Pathologic; Pathology; Physiological; Physiology; Play; Potassium Channel; Property; Regulation; Role; Stroke; Tissues; Work; biophysical analysis; genetic manipulation; insight; large-conductance calcium-activated potassium channels; member; public health relevance; sperm cell; therapeutic target; tumor growth; voltage

 DESCRIPTION (provided by applicant): 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 in excitable tissues. SLO1 is encoded by the kcnma1 (or slo1) gene, which was the first discovered member of the SLO family of four distinct homologous genes. Other SLO family members include the pH-regulated SLO3 channel, expressed exclusively in mammalian sperm and two K+ channels regulated primarily by cytosolic Na+, SLO2.1 and SLO2.2. The ability of SLO family channels to be regulated by cytosolic ions is mediated by the 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. In addition to their regulation by cytosoic ligands, an important component of SLO channel function is their regulation by associated auxiliary subunits. For BK channels, despite being encoded by only a single gene, important functional diversity arises from tissue- specific expression of up to four different auxiliary  subunits (1-4) and a newly identified family of subunits. 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. Of auxiliary subunits, little is known about the locations of expression and physiological roles of 2 and 3 subunits, and even less is known about subunits. This lab uses methods spanning biophysical analysis through whole- animal physiological and behavioral analysis to assess not only topics pertinent to the biophysical and functional properties of channels of different auxiliary subunit composition but also how these channels contribute to electrical excitability in native cells. To probe physiological function in native cells, we utilize genetic knock-out (KO) of specific regulatory channel subunits. Recently, this lab presented the initial work on a 2 KO mouse, and future work will present similar examinations of other regulatory subunits. Such KO models are particular advantageous for providing clues about whether abnormal aspects of channel function or expression may underlie particular disease pathologies. This project is expected to provide new insight into the physiological roles of 2, 3 and 1 auxiliary subunits, and the roles of BK channels containing such subunits.

 描述（由申请人提供）：钙和电压调节的BK（或SLO 1）型K+通道是一种广泛表达的离子通道，影响各种可兴奋组织和可兴奋组织中兴奋性的调节。SLO 1由kcnma 1（或slo 1）基因编码，这是SLO家族4个不同同源基因的第一个发现的成员。其他SLO家族成员包括仅在哺乳动物精子中表达的pH调节的SLO 3通道和主要由细胞溶质Na+调节的两个K+通道SLO 2.1和SLO 2.2。SLO家族通道被胞质离子调节的能力由大的胞质调节结构域介导，该结构域含有特异性离子结合位点，其连接到亚基的孔形成部分。SLO家族通道响应胞质环境变化的能力使得它们独特地适应于在导致胞质离子改变的活性后发挥负反馈作用。除了通过胞质配体进行调节外，SLO通道功能的一个重要组成部分是通过相关辅助亚基进行调节。对于BK通道，尽管仅由单个基因编码，但重要的功能多样性来自多达四种不同的辅助性BK亚基（1-4）和新鉴定的亚基家族的组织特异性表达。 4个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的治疗靶点。在辅助亚基中，对于2和3亚基的表达位置和生理作用知之甚少，对于亚基的了解更少。该实验室使用跨越生物物理分析的方法，通过整个动物的生理和行为分析，不仅评估与不同辅助亚基组成的通道的生物物理和功能特性有关的主题，还评估这些通道如何有助于天然细胞的电兴奋性。为了探测天然细胞中的生理功能，我们利用特定调节通道亚基的基因敲除（KO）。最近，该实验室提出了对2 KO小鼠的初步工作，未来的工作将提出对其他调节亚基的类似检查。这样的KO模型对于提供关于通道功能或表达的异常方面是否可能是特定疾病病理的基础的线索是特别有利的。该项目有望为2，3和1辅助亚基的生理作用以及含有这些亚基的BK通道的作用提供新的见解。