GRK5 Controls SAP97-Dependent Cardiotoxic β1Adrenergic Receptor-CaMKII Signaling in Heart Failure

Abstract

Rationale: Cardiotoxic beta(1)adrenergic receptor (beta(1)AR)-CaMKII (calmodulin-dependent kinase II) signaling is a major and critical feature associated with development of heart failure. SAP97 (synapse-associated protein 97) is a multifunctional scaffold protein that binds directly to the C-terminus of beta(1)AR and organizes a receptor signalosome. Objective: We aim to elucidate the dynamics of beta(1)AR-SAP97 signalosome and its potential role in chronic cardiotoxic beta(1)AR-CaMKII signaling that contributes to development of heart failure. Methods and Results: The integrity of cardiac beta(1)AR-SAP97 complex was examined in heart failure. Cardiac-specific deletion of SAP97 was developed to examine beta(1)AR signaling in aging mice, after chronic adrenergic stimulation, and in pressure overload hypertrophic heart failure. We show that the beta(1)AR-SAP97 signaling complex is reduced in heart failure. Cardiac-specific deletion of SAP97 yields an aging-dependent cardiomyopathy and exacerbates cardiac dysfunction induced by chronic adrenergic stimulation and pressure overload, which are associated with elevated CaMKII activity. Loss of SAP97 promotes PKA (protein kinase A)-dependent association of beta(1)AR with arrestin2 and CaMKII and turns on an Epac (exchange protein directly activated by cAMP)-dependent activation of CaMKII, which drives detrimental functional and structural remodeling in myocardium. Moreover, we have identified that GRK5 (G-protein receptor kinase-5) is necessary to promote agonist-induced dissociation of SAP97 from beta(1)AR. Cardiac deletion of GRK5 prevents adrenergic-induced dissociation of beta(1)AR-SAP97 complex and increases in CaMKII activity in hearts. Conclusions: These data reveal a critical role of SAP97 in maintaining the integrity of cardiac beta(1)AR signaling and a detrimental cardiac GRK5-CaMKII axis that can be potentially targeted in heart failure therapy.