SLO family potassium channels: function and physiology

 描述(申请人提供)：钙和电压调节的BK(或SLO1)型K通道是一种广泛表达的离子通道，影响各种可兴奋组织和可兴奋组织的兴奋性调节。SLO1是由kcnma1(或SLO1)基因编码的，它是SLO家族中发现的第一个成员，由四个不同的同源基因组成。其他SLO家族成员包括pH调节的SLO通道，仅在哺乳动物精子中表达，以及两个主要受胞浆Na调节的K通道，SLO2.1和SLO2.2。SLO家族通道受胞质离子调节的能力是由大的胞质调节域介导的，它包含特定的离子结合部位，连接到亚基的成孔部分。SLO家族通道对胞浆环境变化的反应能力使其独特地适应于在导致胞浆离子变化的活动后扮演负反馈角色。除了受胞质配体的调节外，SLO通道功能的一个重要组成部分是受相关辅助亚基的调节。对于BK通道，尽管只有一个基因编码，但重要的功能多样性来自于组织特异性表达多达四个不同的辅助亚基(1-4)和新发现的亚基家族。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2和3亚基的表达位置和生理作用知之甚少，对亚基的了解更是少之又少。该实验室使用跨越生物物理分析的方法，通过全动物的生理和行为分析，不仅评估与不同辅助亚单位组成的通道的生物物理和功能特性相关的主题，而且评估这些通道如何促进自然细胞的电兴奋性。为了探索天然细胞的生理功能，我们利用特定调控通道亚基的基因敲除(KO)。最近，这个实验室展示了在2KO小鼠上的初步工作，未来的工作将提供对其他调节亚基的类似检查。这种KO模型特别有利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基础的线索。这个项目有望为2、3和1辅助亚基的生理作用以及包含这些亚基的BK通道的作用提供新的见解。

 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.