Steven O. Marx
Heart failure (HF) is a complex syndrome initiated by numerous factors, all of which trigger isympathetic nervous system activation. Initially compensatory, activation of the sympathetic nervous system ultimately worsens cardiac remodeling and promotes arrhythmias. A cornerstone of HF medical therapy, b-blockers broadly attenuate sympathetic nervous system signaling to the heart. Some of the mechanisms underlying the beneficial effects of b-blockers are well described, whereas others remain to be discovered. One logical target is the adrenergic regulation of CaV1.2 channels and Ca2+ influx, as abnormal Ca2+ influx and handling can contribute to the initiation and progression of HF and increased incidence of arrhythmias. Figure 1. Schematic depicting new model of b-adrenergic regulation of Ca2+ channels in heart. Using an enzyme-catalyzed ascorbate-peroxidase (APEX2)-proximity-labeling method [19, 20], we observed that the Ca2+ channel inhibitor Rad, a small G-protein, is enriched near CaV1.2 but is depleted upon exposure to isoproterenol, a b‑adrenergic agonist. At baseline, Rad inhibits CaV1.2 (and CaV1.3); on adrenergic activation, PKA phosphorylates Rad, which releases this inhibition (Fig.1) Disinhibition equals activation.
Three Specific Aims are proposed to propose the role of CaV1.2 channels and their regulation in HF:
To determine the impact of b-adrenergic stimulation of CaV1.2
To determine upstream and downstream regulatory pathways modulating adrenergic stimulation of CaV1.2 in physiological and HF states.
Explore the role of Rad in regulating cardiac function in humans.