The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through G(βγ)-mediated L-type calcium current disinhibition.

Rationale:The Gβγ-sequestering peptide β-adrenergic receptor kinase (βARK)ct derived from the G-protein–coupled receptor kinase (GRK)2 carboxyl terminus has emerged as a promising target for gene-based heart failure therapy. Enhanced downstream cAMP signaling has been proposed as the underlying mechanism for increased β-adrenergic receptor (βAR) responsiveness. However, molecular targets mediating improved cardiac contractile performance by βARKct and its impact on Gβγ-mediated signaling have yet to be fully elucidated. Objective:We sought to identify Gβγ-regulated targets and signaling mechanisms conveying βARKct-mediated enhanced βAR responsiveness in normal (NC) and failing (FC) adult rat ventricular cardiomyocytes. Methods and Results:Assessing viral-based βARKct gene delivery with electrophysiological techniques, analysis of contractile performance, subcellular Ca2+ handling, and site-specific protein phosphorylation, we demonstrate that βARKct enhances the cardiac L-type Ca2+ channel (LCC) current (...