Regulation of Cardiac Calcium Channels by an Autoinhibitory Signaling Complex

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DESCRIPTION (provided by applicant): L-type Ca currents conducted by Cav1.2 channels are responsible for Ca entry that initiates contraction in cardiac muscle, and these channels are therefore the final common pathway for regulation of Ca signaling and contractile force by many different effectors such as neurotransmitters, hormones and drugs, and their receptors. Alterations in L-type Ca currents are crucially involved in cardiovascular disease and therapy. Misregulation of L-type Ca currents contributes to hypertension, and Ca channel antagonist drugs are an important mode of therapy. Ischemic heart disease is often accompanied by angina pectoris, which is also treated with Ca antagonist drugs. Arrhythmias can be generated by altered regulation of L-type Ca currents and by inappropriately timed Ca transients generating early and delayed afterdepolarizations, and Ca antagonist drugs are important in treatment of atrial arrhythmias, (-adrenergic regulation of L-type Ca currents is altered in heart failure. Surprisingly, despite their importance in cardiovascular physiology and pathophysiology, regulation of Cav1.2 channels in cardiac myocytes is not well understood. Because of their key role in regulation of contraction, many intracellular regulators and second messengers converge on these Ca channels and regulate their function, including Mg, cAMP, Ca, and calmodulin. Our work has shown that the sites of action of these second messengers are in the large intracellular C-terminal domain, which represents approximately 30% of the mass of the al subunit. In addition, the C-terminal domain is subject to proteolytic processing, which modulates its function. Thus, the C-terminal domain integrates many kinds of cellular regulatory signals, which together form an integrated intracellular signaling network controlling Ca channel activity. In this project we propose to determine the molecular mechanism and physiological significance of Cav1.2 channel autoinhibition the C-terminal domain, define the mechanism and physiological significance of proteolytic processing of the C-terminal of Cav1.2 channels, and determine the molecular mechanism of regulation of the Cav1.2 channel by the (-adrenergic receptor pathway acting through PKA bound to the channel's distal C-terminal domain by AKAP15. The results of our experiments will be crucial for understanding regulation of Ca and cAMP signaling in the cardiac myocyte and its dysfunction in cardiovascular disease. This information will provide the essential basic science background for translational research aimed at preventing and treating cardiovascular disease.