Structural Changes in BKCa Channels During Gating

超出空间规定。大电导电压和ca2 +激活的K¿通道（BK）是在控制平滑肌张力和神经元兴奋性中起基本作用的膜蛋白。在大多数组织中，它们形成由成孔亚基o_和调节亚基组成的复合物。与其他电压依赖通道类似，BK具有一个电压传感器，主要由$4跨膜段表示。膜上电位的变化使电压传感器位移，使蛋白质的构象发生变化。最终，为了充分的去极化，随后的构象变化使通道进入允许离子传导的状态。我们对调节BK通道开启和关闭的结构知之甚少，也没有关于膜电位变化在BK通道中产生的动态重排的信息。该项目的目的之一是调查BK频道运营的结构变化。o_和13亚基的构象变化将通过通道蛋白残基特异性荧光标记来评估。短期目标是通过识别与激活、失活和失活相关的电压传感运动区域，以及涉及其他通道功能的相对静态区域，获得更现实的BK蛋白视图。此外，还研究了带电残基在孔区的作用。BK通道激活剂目前正在密切研究治疗尿失禁和作为中风神经保护剂。这项研究将有助于为设计新的治疗药物或改进医疗实践中已经采用的药物建立一个框架。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACE PROVIOEO. Large conductance Voltage and Ca 2+ activated K¿ channels (BK) are membrane proteins that play a fundamental role in controlling smooth muscle tone and neuronal excitability. In most of the tissues, they form complexes composed by the pore-forming o_ subunit and by regulatory subunits. Similarly the other voltage dependent ion channels, BK posses a voltage sensor that is mainly represented by the $4 transmembrane segment. Changes in potential across the membrane displace the voltage sensor, producing a conformational change of the protein. Eventually, for adequate depolarizations, the consequent conformational change brings the channel into a state that allows ion conduction. Very little is known about structures that regulate the opening and closing of BK channels, and no information exists about the dynamical rearrangements produced in BK channels by changes in the membrane potential. One of the aims of this project is to investigate the structural changes underlying the operation of BK channel. Conformational changes of both o_ and 13subunits will be assessed by residue- specific fluorescent labeling of the channel protein. The short term objective is to obtain a more realistic view of BK protein by identifying regions of motion that underlie voltage sensing, and that are couple to activation, inactivation and deactivation, and regions of relative staticity, involved in other channel functions. In addition the role of charged residues in pore region will be investigated. BK channel activators are now under close investigation for treatment of urinary incontinence and as stroke neuroprotectant. This study will contribute to set a framework for the design of new therapeutic agents or for the amelioration of the one already adopted by the medical practice. PERFORMANCE SITE ========================================Section End===========================================