Presentation Title

Inhibition of GRK2 Augments Cardiac Beta2-Adrenergic Receptor-Dependent Contractility and Survival

Format

Event

Start Date

10-2-2012 12:00 AM

Abstract

Objective. Investigation of the effect of inhibition of cardiac GRK2 on ß2AR pro-contractile and prosurvival signaling in vivo. Background. ß1- and ß2-adrenergic receptors (ßARs) are G-protein coupled receptors (GPCRs) that play clearly distinct roles in cardiac physiology/pathology. This might be explained by differences in assembly of macromolecular signaling complexes: ß1AR forms a signaling complex with phosphodiesterase (PDE) type 4D8 directly, and agonist binding dissociates this complex. Conversely, GPCR kinase (GRK)2-induced ß2AR phosphorylation leads to recruitment of a complex consisting of ßarrestin (ßarr), a universal GPCR adapter/scaffolding molecule, and another PDE4D variant, PDE4D5. This PDE4D recruitment is postulated to constrain ß2AR pro-contractile signaling by limiting compartmentalization of 3'-5'-adenosine monophosphate signaling. Methods. We crossed ß1AR knockout (B1KO) mice, which do not express ß1AR, with M27 mice, which overexpress, specifically in cardiac myocytes, the GRK2 inhibitor GRK2ct. By blocking GRK2-mediated phosphorylation, ßarrdependent PDE4D recruitment to ß2AR is prevented. We studied the offspring both under normal conditions and after surgically induced myocardial infarction (MI). Results. Contractility was significantly augmented in M27/B1KO mice compared to B1KO's, both in healthy mice and at 4 weeks after MI, and M27/B1KO hearts displayed significantly less membrane recruitment of PDE4D compared to B1KO hearts, indicating less ß2AR-PDE4D interaction. Additionally, survival of M27/B1KO mice overexpressing the GRK2 inhibitor was increased after MI. Conclusion. Cardiac GRK2 inhibition by GRK2ct increases ß2AR-dependent contractility and survival both normally and in post-MI heart failure. Grants. This study 33 was funded in part by a Scientist Development Grant from the American Heart Association (AHA) and an HPD Research Grant, both to A.L.

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Feb 10th, 12:00 AM

Inhibition of GRK2 Augments Cardiac Beta2-Adrenergic Receptor-Dependent Contractility and Survival

Objective. Investigation of the effect of inhibition of cardiac GRK2 on ß2AR pro-contractile and prosurvival signaling in vivo. Background. ß1- and ß2-adrenergic receptors (ßARs) are G-protein coupled receptors (GPCRs) that play clearly distinct roles in cardiac physiology/pathology. This might be explained by differences in assembly of macromolecular signaling complexes: ß1AR forms a signaling complex with phosphodiesterase (PDE) type 4D8 directly, and agonist binding dissociates this complex. Conversely, GPCR kinase (GRK)2-induced ß2AR phosphorylation leads to recruitment of a complex consisting of ßarrestin (ßarr), a universal GPCR adapter/scaffolding molecule, and another PDE4D variant, PDE4D5. This PDE4D recruitment is postulated to constrain ß2AR pro-contractile signaling by limiting compartmentalization of 3'-5'-adenosine monophosphate signaling. Methods. We crossed ß1AR knockout (B1KO) mice, which do not express ß1AR, with M27 mice, which overexpress, specifically in cardiac myocytes, the GRK2 inhibitor GRK2ct. By blocking GRK2-mediated phosphorylation, ßarrdependent PDE4D recruitment to ß2AR is prevented. We studied the offspring both under normal conditions and after surgically induced myocardial infarction (MI). Results. Contractility was significantly augmented in M27/B1KO mice compared to B1KO's, both in healthy mice and at 4 weeks after MI, and M27/B1KO hearts displayed significantly less membrane recruitment of PDE4D compared to B1KO hearts, indicating less ß2AR-PDE4D interaction. Additionally, survival of M27/B1KO mice overexpressing the GRK2 inhibitor was increased after MI. Conclusion. Cardiac GRK2 inhibition by GRK2ct increases ß2AR-dependent contractility and survival both normally and in post-MI heart failure. Grants. This study 33 was funded in part by a Scientist Development Grant from the American Heart Association (AHA) and an HPD Research Grant, both to A.L.