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GRK5 Controls SAP97-Dependent Cardiotoxic β 1 Adrenergic Receptor-CaMKII Signaling in Heart Failure.
- Source :
-
Circulation research [Circ Res] 2020 Aug 28; Vol. 127 (6), pp. 796-810. Date of Electronic Publication: 2020 Jun 08. - Publication Year :
- 2020
-
Abstract
- Rationale: Cardiotoxic β <subscript>1</subscript> adrenergic receptor (β <subscript>1</subscript> 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 β <subscript>1</subscript> AR and organizes a receptor signalosome.<br />Objective: We aim to elucidate the dynamics of β <subscript>1</subscript> AR-SAP97 signalosome and its potential role in chronic cardiotoxic β <subscript>1</subscript> AR-CaMKII signaling that contributes to development of heart failure.<br />Methods and Results: The integrity of cardiac β <subscript>1</subscript> AR-SAP97 complex was examined in heart failure. Cardiac-specific deletion of SAP97 was developed to examine β <subscript>1</subscript> AR signaling in aging mice, after chronic adrenergic stimulation, and in pressure overload hypertrophic heart failure. We show that the β <subscript>1</subscript> 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 β <subscript>1</subscript> 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 β <subscript>1</subscript> AR. Cardiac deletion of GRK5 prevents adrenergic-induced dissociation of β <subscript>1</subscript> AR-SAP97 complex and increases in CaMKII activity in hearts.<br />Conclusions: These data reveal a critical role of SAP97 in maintaining the integrity of cardiac β <subscript>1</subscript> AR signaling and a detrimental cardiac GRK5-CaMKII axis that can be potentially targeted in heart failure therapy. Graphical Abstract: A graphical abstract is available for this article.
- Subjects :
- Animals
Apoptosis
Cells, Cultured
Cyclic AMP-Dependent Protein Kinases metabolism
Discs Large Homolog 1 Protein genetics
Disease Models, Animal
Excitation Contraction Coupling
G-Protein-Coupled Receptor Kinase 5 genetics
Guanine Nucleotide Exchange Factors metabolism
Heart Failure genetics
Heart Failure pathology
Heart Failure physiopathology
Humans
Male
Mice, Inbred C57BL
Mice, Knockout
Myocardial Contraction
Myocytes, Cardiac pathology
beta-Arrestin 1 metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism
Discs Large Homolog 1 Protein metabolism
G-Protein-Coupled Receptor Kinase 5 metabolism
Heart Failure enzymology
Myocytes, Cardiac enzymology
Receptors, Adrenergic, beta-1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4571
- Volume :
- 127
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Circulation research
- Publication Type :
- Academic Journal
- Accession number :
- 32507058
- Full Text :
- https://doi.org/10.1161/CIRCRESAHA.119.316319