Molecular regulation of calcium-activated (BK) potassium channels

描述（由申请人提供）：电兴奋性主要由选择性传导不同离子的离子通道蛋白介导。酶对离子通道的调节是赋予其生物多样性和响应生理变化的核心。能够感知电信号和化学信号的能力赋予离子通道在不同生物系统中的关键作用。大电导钙激活（BK）钾通道由膜电位电压和细胞质钙浓度门控。由于动作电位是膜兴奋性的中心，细胞内钙离子浓度与各种生物过程相耦合，因此BK通道的功能作用是多样的，具有重要意义。编码功能多样性的一个重要机制是通过孔形成亚基（称为α亚基）的选择性剪接。目前对BK结构和功能的了解几乎完全基于对一种称为BK_ERL的C末端剪接变体的研究。将天然BK通道特性与BK亚基的相应分子同种型联系起来的直接证据尚不足以完全确定ERL同种型是体内功能的最重要形式。另一种C-末端剪接变体BK_DEC具有不同于通常研究的ERL形式的额外61个氨基酸。我们现在表明，这一地区是密集挤满了功能基序，并代表了酶组装域招募了一些酶和调节因子。本研究旨在研究新发现的由BKJDEC组织的酶复合物。具体目标包括这些新鉴定的蛋白质复合物的生物化学、细胞生物学和功能表征。BK通道对于从激素分泌到控制神经元放电特性的各种生物过程至关重要。已经开发了药物来调节这些通道的活性，以治疗人类疾病，如中风，癫痫和其他神经系统疾病。因此，了解不同BK亚型的功能和生理学具有治疗学重要性。

DESCRIPTION (provided by applicant): Electrical excitability is primarily mediated by ion channel proteins which selectively conduct different ions. Regulation of ion channels by enzymes is central to confer their biological diversity and respond to physiological changes. The ability to sense both electrical signals and chemical signals endows an ion channel critical roles in diverse biological systems. The large conductance calcium-activated (BK) potassium channels are gated both by membrane potential voltage and by cytoplasmic calcium concentration. Because action potential is central to membrane excitability and the intracellular calcium concentration is coupled with a wide variety of biological processes, the functional roles of BK channels are accordingly diverse and of great significance. One important mechanism of coding functional diversity is through alternative splicing of pore-forming subunit, known as alpha subunit. The current understanding of BK structure and function is, almost exclusively, based on studies of one type of C-terminal splice variants known as BK_ERL. The direct evidence linking native BK channel properties and the corresponding molecular isoforms of BK subunits is not yet adequate to fully establish that the ERL isoform is the most important form for the in vivo function. Another C-terminal splice variant, BK_DEC, has additional 61 aa distinct from commonly studied ERL form. We now show this region is densely packed with functional motifs and represents an enzymatic assembly domain recruiting a number of enzymes and regulatory factors. This research proposal is aimed at investigating newly identified enzymatic complexes organized by BKJDEC. The specific aims include biochemical, cell biological and functional characterization of these newly identified protein complexes. BK channels are critical for a variety of biological processes ranging from hormone secretion to control of neuronal firing properties. Drugs have been developed to regulate these channels' activity to treat human diseases such as stroke, epilepsy and other neurological disorders. Thus, understanding of the function and physiology of different BK subtypes is of therapeutics importance.