Mechanisms and Therapeutic Role of C-terminus of Cav1.3 L-type Calcium Channel in the Heart

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In the heart, there are two types of L-type calcium channels, the classical Cav1.2 and the novel less characterized Cav1.3. They both convert cell-membrane depolarization into calcium transients and initiate excitation-contraction coupling. Interestingly, Cav1.3 is expressed in the supraventricular tissue and ventricles of the fetal and neonatal hearts but not in the ventricles of the adult heart. Cav1.3 also has an extended C-terminus. Relevant to this application is that our preliminary data demonstrate that the C-terminus of Cav1.3 is mobile and functions as a transcription auto-enhancer of its own Cav1.3 gene. This unique endogenous property can be leveraged to generate inotropic force necessary to restore cardiac function in the setting of heart failure which is highly prevalent in Veterans. Here we will test, for the first time, the hypothesis that the translocation of the Cav1.3 C-terminus mobile fragment to the nucleus will upregulate Cav1.3 gene expression at specific promoter region(s) and thus provide additional calcium entry into the cardiac myocyte resulting in improved cardiac function in a murine model of heart failure. This hypothesis will be tested in three aims: Aim 1: Investigate the regulation of gene expression by C-terminus of Cav1.3 in a native environment; Aim 2: Determine the mechanisms of Cav1.3 C-terminus regulation of Cav1.3 gene promoter activity; Aim 3: Investigate the potential therapeutic impact of Cav1.3 C-terminus in heart failure. Studies will be carried out by a combination of electrophysiological (patch-clamp and optical mapping), RNA-seq, biochemical, echocardiography and histology, in in-vivo and ex-vivo hearts. The findings from this work will provide a novel mechanism by which Cav1.3 L-type calcium channel acts not only as a conventional ion pore but also as a transcription factor regulating gene expression and cell function via its C-terminus. The ability of the C-terminus of Cav1.3 to upregulate its own gene can be exploited for the development of novel inotropic therapies for heart failure which is prevalent in Veterans.