Ca2+ Regulation of Ca Channels

描述(由申请人提供)：积极和消极的反馈是 对信息网络来说，钙信号是至关重要的，钙信号也不例外。 在过去的几年里，涉及钙调节的反馈的描述 电压门控钙通道的范围从根本上发生了变化， 自然，以及潜在的机制。在高电压激活的家庭中 (HVA)钙通道(L型、P/Q型、N型和R型)，仅L型广泛 以强烈的Ca22+调控而闻名，这一调控被认为 由Ca22+直接与通道结合而产生。但这个简单的观点有 开始溶解。它不是钙离子直接作用于通道，而是 钙调素(CaM)与L类通道的相互作用触发钙依赖 失活(CDI)，也许还有促进(CDF)。而且，这种方式 CAM调节钙通道是不寻常的，只显示出意想不到的能力 在其他地方很少看到。更有趣的是，Cam与L的互动类型 渠道依赖于在很大程度上保守的独特的结构特征 在其他HVA通道中，提示它们的钙调节可能不是休眠的。 最近，P/Q型通道已经表现出钙/钙调理作用。整体而言 因此，目标是推动对HVA中钙调节的发现 渠道家族，并测试通用的整体监管机制。 电生理学，重组钙通道的表达，分子 生物学/生物化学和基于FRET的显微镜结合在四个目标中，每个目标 以功能和/或机械发现的显著领域为目标。(1)至 阐明L型钙离子调控的结构机制 通过Cam的频道。(2)提炼P/Q型(案例)的功能维度 约2.1)钙离子对钙通道的调节，并阐明基于结构的 这种监管背后的机制。(3)发现钙离子对细胞的调节作用。 其他HVA通道(N型和R型；分别约为2.2和2.3)， 并为任何这样的调控描绘基本的分子元件。(4)至 确定每种O约亚基的羧基尾部是否为钙离子 调节模块--可以赋予钙离子特定的通道表型的模块 关于主干的国外频道的规定。这些目标带来了新的前景 神经生物学的维度，并可能为药物发现提供基础 目标是精神疾病。

DESCRIPTION (provided by applicant): Feedback, both positive and negative, is inherently critical to information networks, and Ca+ signaling is no exception. Over the past few years, the description of feedback involving Ca2+ regulation of voltage-gated Ca channels has shifted fundamentally in terms of scope, nature, and underlying mechanism. Within the family of high-voltage-activated (HVA) Ca channels (L-, P/Q-, N-, and R-type), only the L-type was widely renowned for strong Ca22+ regulation, and this regulation was believed to result from Ca22+ binding directly to the channel. But this simple view has begun to dissolve. Rather than Ca2+ acting directly on channels, it is calmodulin (CaM) interaction with L-type channels that triggers Ca2+-dependent inactivation (CDI), and perhaps facilitation (CDF). Moreover, the way in which CaM modulates Ca channels is unusual, showing unexpected capabilities only sparingly glimpsed elsewhere. Of further interest, CaM interaction with L-type channels relies on distinctive structural hallmarks that are largely conserved in other HVA channels, hinting that their Ca2+ regulation may not be dormant. Already, P/Q-type channels have recently shown Ca2+/CaM regulation. The overall goals are therefore to drive discovery of Ca2+ regulation across the HVA channel family, and to test for a common overall regulatory mechanism. Electrophysiology, expression of recombinant Ca channels, molecular biology/biochemistry, and FRET-based microscopy are combined in four aims, each targeting a salient area of functional and/or mechanistic discovery. (1) To clarify structural mechanisms for Ca2+ regulation of L-type (Cay 1.2) Ca channels via CaM. (2) To refine the functional dimensions of P/Q-type (Ca about2.1) Ca channel regulation by Ca2+, and to elucidate structure-based mechanisms underlying such regulation. (3) To discover Ca2+ regulation of the other HVA channels (N- and R-type; Ca about2.2 and Ca about2.3, respectively), and to delineate essential molecular elements for any such regulation. (4)To determine whether the carboxy tail of each type of o about subunit is a Ca2+ regulatory module-one that can confer a channel-specific phenotype of Ca2+ regulation to a foreign channel o about backbone. These aims promise new dimensions of neurobiology, and may provide the basis for drug discovery targeting psychiatric illness.