Structure and function of voltage-gated calcium channels

描述(由申请人提供)：本项目的长期目标是对电压门控钙通道(Cav)的功能和调节有一个高分辨率的了解。这些分子开关在心脏动作电位的传播、神经递质的释放、肌肉收缩、钙依赖基因转录和突触传递中起着关键作用。钙内流是细胞内信号通路的有效激活剂，但过量则具有毒性。因此，它进入细胞受到严格的监管。CAV是活性依赖性钙内流的主要来源，具有多种自我调节机制，包括：电压依赖性失活(VDI)、钙依赖性促进(CDF)和钙依赖性失活(GDI)。我们正在研究这些现象的分子基础。这些现象严重依赖于孔道形成亚单位与调节通道活动的细胞质成分之间的相互作用。由于研究哺乳动物膜蛋白结构的困难，我们致力于了解两个关键的细胞质成分，Cav P-亚基和钙感受器的功能，这两个组分对通道组装和钙依赖调节非常重要，并且在协调VDI、CDF和GDI过程中发挥重要作用。我们正在寻求一种多学科的方法，包括生化、生物物理、X射线结晶学和电生理测量来剖析CAV的功能。 由于其在人体生理中的重要作用，CAV是治疗心律失常、高血压、充血性心力衰竭、癫痫和慢性疼痛的药物的靶点。因此，在原子水平上详细了解它们的结构和作用机制将极大地帮助开发有价值的治疗药物来治疗广泛的人类心脏和神经问题。

DESCRIPTION (provided by applicant): The long-term goals of this project are to develop a high-resolution understanding of voltage-gated calcium channel (Cav) function and regulation. These molecular switches play pivotal roles in cardiac action potential propagation, neurotransmitter release, muscle contraction, calcium-dependent gene-transcription, and synaptic transmission. Calcium influx is a potent activator of intracellular signaling pathways but is toxic in excess. As a result, its entry into cells is tightly regulated. Cavs are major sources of activity-dependent calcium influx and possess a number of mechanisms that allow them to self-regulate including: voltage-dependent inactivation (VDI), calcium dependent facilitation (CDF), and calcium dependent inactivation (GDI). We are investigating the molecular basis of these phenomena. These phenomena depend critically on interactions of the pore-forming subunit with the cytoplasmic components that regulate channel activity. Due to the difficulties in studying mammalian membrane protein structure, our efforts are directed at understanding the function of two critical cytoplasmic components, the Cav P-subunit and calcium sensors, that are important for channel assembly and calcium-dependent regulation and that play major roles in orchestrating VDI, CDF, and GDI processes. We are pursuing a multidisciplinary approach that includes biochemical, biophysical, X-ray crystallographic, and electrophysiological measurements to dissect Cav function. Because of their important role in human physiology, Cavs are the targets for drugs with great utility for the treatment of cardiac arrhythmias, hypertension, congestive heart failure, epilepsy, and chronic pain. Thus, understanding their structures and mechanisms of action at atomic level detail should greatly assist the development of valuable therapeutic agents for a wide range of human cardiac and neurological problems.