Journal article
GRK5 Controls SAP97-Dependent Cardiotoxic beta(1)Adrenergic Receptor-CaMKII Signaling in Heart Failure
Circulation research, Vol.127(6), pp.796-810
08/28/2020
DOI: 10.1161/CIRCRESAHA.119.316319
PMCID: PMC7484403
PMID: 32507058
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.
Details
- Title: Subtitle
- GRK5 Controls SAP97-Dependent Cardiotoxic beta(1)Adrenergic Receptor-CaMKII Signaling in Heart Failure
- Creators
- Bing Xu - VA Northern California Health Care SystemMinghui Li - University of California, DavisYing Wang - University of California, DavisMeimi Zhao - University of California, DavisStefano Morotti - University of California, DavisQian Shi - University of California, DavisQingtong Wang - University of California, DavisFederica Barbagallo - University of California, DavisJian-Peng Teoh - University of California, DavisGopireddy R. Reddy - University of California, DavisElizabeth F. Bayne - University of Wisconsin–MadisonYongming Liu - University of California, DavisAo Shen - University of California, DavisJose L. Puglisi - University of California, DavisYing Ge - University of Wisconsin–MadisonJi Li - University of South FloridaEleonora Grandi - University of California, DavisMadeline Nieves-Cintron - University of California, DavisYang K. Xiang - University of California, Davis
- Resource Type
- Journal article
- Publication Details
- Circulation research, Vol.127(6), pp.796-810
- Publisher
- Lippincott Williams & Wilkins
- DOI
- 10.1161/CIRCRESAHA.119.316319
- PMID
- 32507058
- PMCID
- PMC7484403
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Number of pages
- 15
- Grant note
- American Heart Association postdoctoral fellowship; American Heart Association HL127764; HL147263; R01HL131517; K99HL138160 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 15SDG24910015 / American Heart Association 01BX002900 / VA Merit grant
- Language
- English
- Date published
- 08/28/2020
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984360146902771
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