Modification of In Vivo Cardiac Performance by Intracoronary Gene Transfer of β-Adrenergic Receptor Signaling Components

Abstract

Alterations in β-adrenergic receptor (βAR) signaling typically occur in cardiomyocytes from hearts progressing toward failure (1). Regulation of G-protein-coupled βARs mostly involves phosphorylation of agonist-occupied receptors by a βAR kinase (βARK1), leading to desensitization. This process also requires a second protein, β-arrestin, which binds to phosphorylated receptors and sterically interdicts further coupling. βARK1, also known as GRK2, is primarily a cytosolic enzyme that must translocate to the membrane in order to phosphorylate its receptor substrate. This is accomplished through a direct physical interaction between the GRK and the βγ-subunits of G-proteins (G_βγ) (2,3). The G_βγ-binding site on βARK1 has been mapped to a region located toward the carboxyl terminus of the enzyme, and a peptide derived from this region (βARKct) can act as an effective in vivo βARK1 inhibitor. The βARKct represents the last 194 amino acids of βARK1 containing the G_βγ-binding domain (2) and has been utilized in transgenic mice to inhibit the in vivo activity of βARK1 (4). Moreover, these mice present with enhanced cardiac contractility that has led to the rescue of several mouse models of cardiomyopathy (4,5).