MOLECULAR CORRELATES OF HUMAN CA2+ CHANNEL REGULATION

描述（改编自研究者摘要）：本研究提案是 旨在推进对异质性、表达模式和 调节C类电压门控L型Ca 2+的分子相关物 通道使用分子和电生理方法。长期 目的是继续研究结构功能的变化， 选择性剪接导致的Ca2+通道孔形成α 1C亚基，以及 探索通道失活的受影响分子相关性。的 通道失活的分子机制将使用两个 鉴定了α 1C通道亚型，一种失活，另一种失活。 缺乏Ca2+依赖性失活。该假说指出， Ca2+诱导的通道失活是由以下相互作用介导的： 最近发现的具有Ca2+传感器的孔隙相关位点 α 1C的胞质C末端尾。为了检测与 通过Ca2+传感器调节α 1C通道，P.I.将调查 它们是否被孔渗透和细胞质 Ca2+。研究将确定Ca2+传感器是否有助于机制 控制通道的电导率和离子选择性。私家侦探将 直接识别Ca2+传感器控制的分子靶标 失活门。此外，PI。将检查哪种Ca2+传感器 alpha1C通道与ryanodine参与局部Ca2+信号传导 心肌细胞的受体。结果可能会提供重要的见解， Ca2+信号转导的基本原理 偶联在人类心脏和血管肌肉细胞，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.