MOLECULAR CORRELATES OF HUMAN CA2+ CHANNEL REGULATION

人类 CA2 通道调节的分子相关性

• 批准号: 6537578
• 负责人: MARTIN MORAD
• 金额: $ 36.37万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537578
• 关键词: Xenopus oocyte; calcium channel; calcium flux; calcium indicator; cardiac myocytes; cell line; peptide library; pore forming protein; protein isoforms; protein structure function; transfection; voltage /patch clamp; voltage gated channel

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.

描述（改编自研究者摘要）：本研究提案是 旨在推进异质性、表达模式和 C 类电压门控 L 型 Ca2+ 调节的分子关联 使用分子和电生理学方法的通道。长期来看 目标是继续研究结构功能的改变 Ca2+通道成孔α1C亚基由于选择性剪接，并且 探索通道失活受影响的分子相关性。这 将使用其中的两种方法来研究通道失活的分子机制 鉴定出 alpha1C 通道亚型，一种被剥夺失活，另一种被剥夺 缺乏 Ca2+ 依赖性失活。该假设指出 Ca2+ 诱导的通道失活是通过以下相互作用介导的 最近在 α1C 的细胞质 C 末端尾部。检查分子相关性 Ca2+ 传感器对 alpha1C 通道的调节，P.I.将调查 它们是否被孔渗透和细胞质靶向 钙2+。研究将确定 Ca2+ 传感器是否有助于该机制 控制通道的电导和离子选择性。 P.I.将要 直接识别 Ca2+ 传感器控制的分子靶点 失活门。此外，P.I.将检查哪个 Ca2+-传感器 α1C 通道参与兰尼碱的局部 Ca2+ 信号传导 心肌细胞的受体。结果可能会给人们带来重要的见解 Ca2+ 信号传导的基本原理是兴奋-收缩的基础 耦合人类心肌细胞和血管肌细胞并提供有用的线索 用于分子诊断和药物开发。