Adrenergic Regulation of Cardiac CaV1.2 via Direct Phosphorylation and the GTPase RAD

Abstract

Dysregulation of the cardiac fight-or-flight response has been linked to chronic heart failure and arrhythmic disorders. The L-type calcium channel CaV1.2 has a central role in mediating the cardiac fight-or-flight response, but the precise molecular mechanisms that transduce adrenergic stimulation to increased cardiac output are not completely characterized. This work seeks to address fundamental mechanistic questions related to the regulation of CaV1.2 during the cardiac fight-or-flight response, and thus lay the groundwork for next-generation therapies targeting the ?-adrenergic-CaV1.2 signaling axis. I have specifically focused on a critical question in the field: is CaV1.2 activity primarily regulated by direct phosphorylation during the fight-or-flight response, or through other molecular mediators? I report here that direct phosphorylation of the C-Terminal Domain of CaV1.2 has an important role in cardiac function and CaV1.2 activity, and that the small GTPase RAD co-regulates the channel alongside direct phosphorylation. These findings indicate that the molecular mechanism of the cardiac fight-or-flight response is characterized by convergence of the direct phosphorylation and RAD pathways to co-regulate CaV1.2 activity.