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）功能和调节进行高分辨率的了解。这些分子开关在心脏动作电位传播、神经递质释放、肌肉收缩、钙依赖性基因转录和突触传递中起关键作用。钙内流是细胞内信号传导途径的有效激活剂， 是有毒的。因此，它进入细胞受到严格的调控。CaV是活性依赖性钙内流的主要来源，并具有许多允许其自我调节的机制。这些机制主要依赖于孔形成亚基与调节通道活性的细胞质蛋白（如钙传感器蛋白钙调素和CaBP 1）的相互作用。我们正在研究这些现象的分子基础。由于研究哺乳动物膜蛋白结构的非凡挑战，我们的努力是针对了解细胞质组分和钙传感器蛋白之间的相互作用的功能。我们正在追求一个多学科的方法，包括生物化学，生物物理，X射线晶体学，和电生理测量解剖CaV功能连同功能研究和分子动力学模拟，以了解离子选择性的结构基础。由于它们在人体生理学中的重要作用，CaV是用于治疗心律失常、高血压、充血性心力衰竭、癫痫和慢性疼痛的药物的靶标。因此，了解它们的结构和原子水平上的作用机制，将大大有助于开发有价值的治疗药物，用于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 f activity-dependent calcium influx and possess a number of mechanisms that allow them to self-regulate. These mechanisms depend critically on interactions of the pore-forming subunit with cytoplasmic proteins that regulate channel activity such as the calcium sensor proteins calmodulin and CaBP1. We are investigating the molecular basis of these phenomena. Due to the extraordinary challenges in studying mammalian membrane protein structure, our efforts are directed at understanding the function of the interactions between cytoplasmic components and the calcium sensor proteins. We are pursuing a multidisciplinary approach that includes biochemical, biophysical, X-ray crystallographic, and electrophysiological measurements to dissect CaV function together with functional studies and molecular dynamics simulations to understand the structural basis of ion selectivity. 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.