Structural basis of Ca2+ channel function and regulation

高电压激活（HVA）钙通道是多种生物过程所必需的， 基因调控和细胞生长到神经递质释放和肌肉收缩。它们是由 几种亚基，包括α 1、α 2-δ和β。虽然β亚基只是一种辅助性的 亚基，它是必不可少的运输通道复合物的表面膜和适当的 渠道的功能。其他信号蛋白，如G蛋白和Rem/Rad/Gem（Kir）（RGK）家族 小GTP酶，通过间接或直接与HVA钙通道相互作用来调节HVA钙通道的活性。 β亚基因此，β亚单位是至关重要的调节钙的大小和动力学 可兴奋细胞中的信号。我们的小组和另外两个小组最近获得了高分辨率的晶体 β亚基与α 1亚基中的主要结合配偶体复合的结构。这 研究计划将结合联合收割机x射线晶体学，生物化学和电生理学，进一步研究 结构和功能的β亚基及其与其他蛋白质的相互作用，使用新的结构， 一张蓝图我们将研究：（1）HVA钙调节的结构和生物物理机制 （2）β亚基对HVA钙通道的调节与β亚基对HVA钙通道的调节之间的相互作用。 亚基和G蛋白β-γ亚基;（3）调节的结构和生物物理机制 RGK GTP酶对HVA钙通道的影响β亚基的突变会导致人类疾病， 作为特发性全身性癫痫和发作性共济失调，RGK GT3基因突变与 充血性心力衰竭因此，这些研究不仅可以提供新的见解， 钙通道功能和调节的机制，以及治疗糖尿病的新的治疗策略 神经和心血管疾病。

High voltage-activated (HVA) calcium channels are essential for diverse biological processes ranging from gene regulation and cell growth to neurotransmitter release and muscle contraction. They are made up of several subunits, including alphal, alpha2-delta and beta. Although the beta subunit is only an auxiliary subunit, it is essential for trafficking the channel complex to the surface membrane and for the proper function of the channel. Other signaling proteins, such as G proteins and Rem/Rad/Gem(Kir) (RGK) family of small GTPases, regulate the activity of HVA calcium channels by either indirectly or directly interact with the beta subunit. Thus, the beta subunit is crucial for regulating the magnitude and kinetics of calcium signaling in excitable cells. Our group and two other groups have recently obtained high-resolution crystal structures of the beta subunit in complex with its primary binding partner in the alpha 1 subunit. This research proposal will combine x-ray crystallography, biochemistry and electrophysiology to further study the structure and function of the beta subunit and its interactions with other proteins, using the new structures as a blueprint. We will study: (1) the structural and biophysical mechanisms of regulation of HVA calcium channels by the beta subunit; (2) the interplay between regulation of HVA calcium channels by the beta subunit and G protein beta-gamma subunit; and (3) the structural and biophysical mechanisms of regulation of HVA calcium channels by the RGK GTPases. Mutations in the beta subunit cause human diseases such as idiopathic generalized epilepsy and episodic ataxia and a mutation in a RGK GTPase has been linked to congestive heart failure. These studies therefore may not only provide new insights into the basic mechanisms of calcium channel function and regulation but also new therapeutic strategies for treating neurological and cardiovascular diseases.