MOLECULAR CORRELATES OF HUMAN CA2+ CHANNEL REGULATION

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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.