MOLECULAR CORRELATES OF HUMAN CA2+ CHANNEL REGULATION

描述(改编自《调查者摘要》)：这项研究提案是 旨在推进对异质性、表达模式和 调节C类电压门控L型钙离子的分子机制 使用分子和电生理方法的通道。长期的 目的是继续研究血管内皮细胞的结构-功能改变。 由于选择性剪接而导致的Ca~(2+)通道成孔α1C亚基，以及 探索受影响的分子与通道失活的相关性。这个 通道失活的分子机制将使用两个 已鉴定的Alpha1C通道亚型，一种被剥夺了失活状态，另一种被剥夺了活性 缺乏钙依赖的失活。这一假设表明 钙离子诱导的通道失活是由钙离子与钙离子相互作用引起的 新近发现的孔隙伴生部位(S)和钙离子传感器 Alpha1C的细胞质C末端尾巴。为了研究分子间的关联 通过钙离子传感器对Alpha1C通道的调节，P.I.将调查 它们是否是穿孔和胞浆的不同靶点 Ca2+。研究将确定钙离子传感器是否参与了这一机制 控制通道的电导和离子选择性。私家侦探会 直接识别S控制的钙离子传感器的分子靶标 失活门。此外，P.I.将检查 Alpha1C通道与兰尼定共同参与局部钙信号转导 心肌细胞的受体。结果可能会给我们提供重要的见解 钙离子信号转导兴奋收缩的基本原理 人心肌和血管肌细胞的偶联并提供有用的线索 用于分子诊断和药物开发。

DESCRIPTION (Adapted from Investigator's Abstract): This research proposal is designed to advance a study of heterogeneity, patterns of expression and molecular correlates for regulation of the class C voltage-gated L-type Ca2+ channel using molecular and electrophysiological approaches. The long-term objective is to pursue the study of the structure-functional alterations of the Ca2+ channel pore-forming alpha 1C subunit due to alternative splicing, and to explore the affected molecular correlates for the channel inactivation. The molecular mechanisms of channel inactivation will be studied using two of the identified alpha1C channel isoforms, one deprived of inactivation and the other lacking the Ca2+-dependent inactivation. The hypothesis states that Ca2+-induced inactivation of the channel is mediated by the interaction of the pore-associated site(s) with Ca2+ sensors recently discovered in the cytoplasmic C-terminal tail of alpha1C. To examine molecular correlates for the regulation of the alpha1C channel by Ca2+ sensors, the P.I. will investigate whether they are differentially targeted by the pore-permeating and cytoplasmic Ca2+. Studies will determine if Ca2+ sensors contribute to the mechanisms controlling the conductance and ion selectivity of the channel. The P.I. will directly identify the molecular target for the Ca2+ sensor(s)-controlled inactivation gates. In addition, the P.I. will examine which Ca2+-sensor of the alpha1C channel is involved in the local Ca2+ signaling with the ryanodine receptor of the cardiac myocytes. Results may give important insights into the fundamental principles of Ca2+ signaling underlying excitation-contraction coupling in human cardiac and vascular muscle cells and provide useful clues for the molecular diagnostics and drug developments.