Structural basis of Ca2+ channel function and regulation

高压激活(HVA)钙通道在多种生物过程中是必不可少的，包括 基因调控和细胞生长对神经递质释放和肌肉收缩的影响。它们由以下几部分组成 几个亚基，包括α、α2-增量和β。尽管β亚基只是一种辅助 亚单位，它是必不可少的运输通道复合体到表膜和适当的 通道的功能。其他信号蛋白，如G蛋白和Rem/Rad/Gem(KIR)(RGK)家族 通过间接或直接相互作用来调节HVA钙通道的活性 β亚基。因此，β亚基对调节钙的大小和动力学至关重要。 在可兴奋细胞中发出信号。我们的团队和另外两个团队最近获得了高分辨率的晶体 β亚基的结构与其在α1亚基中的主要结合伙伴形成复合体。这 研究计划将结合X射线结晶学、生物化学和电生理学来进一步研究 β亚基的结构和功能及其与其他蛋白质的相互作用，使用新的结构作为 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亚基调节HVA钙通道的相互作用 以及(3)结构和生物物理调控机制。 RGK GTP酶对HVA钙通道的影响。β亚基的突变会导致人类疾病，如 作为特发性全身性癫痫和发作性共济失调，RGK GTP酶突变与 充血性心力衰竭因此，这些研究不仅可能为基本的 钙通道的作用和调节机制及其治疗新策略 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.