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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:

Aim 1:
To determine the impact of b-adrenergic stimulation of CaV1.2 

Aim 2: 
To determine upstream and downstream regulatory pathways modulating adrenergic stimulation of CaV1.2 in physiological and HF states.

Aim 3: 
Explore the role of Rad in regulating cardiac function in humans.

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