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GRK5 Controls SAP97-Dependent Cardiotoxic ß1 Adrenergic Receptor-CaMKII Signaling in Heart Failure.
Xu, Bing; Li, Minghui; Wang, Ying; Zhao, Meimi; Morotti, Stefano; Shi, Qian; Wang, Qingtong; Barbagallo, Federica; Teoh, Jian-Peng; Reddy, Gopireddy R; Bayne, Elizabeth F; Liu, Yongming; Shen, Ao; Puglisi, Jose L; Ge, Ying; Li, Ji; Grandi, Eleonora; Nieves-Cintron, Madeline; Xiang, Yang K.
Affiliation
  • Xu B; From the VA Northern California Health Care System, Mather, CA (B.X., Y.K.X.).
  • Li M; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Wang Y; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Zhao M; Nanjing First Hospital, Nanjing Medical University, China (M.L.).
  • Morotti S; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Shi Q; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Wang Q; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Barbagallo F; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Teoh JP; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Reddy GR; Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, China (Q.W.).
  • Bayne EF; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Liu Y; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Shen A; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Puglisi JL; Department of Chemistry, University of Wisconsin-Madison (E.F.B., Y.G.).
  • Ge Y; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Li J; Shuguang Hospital, Shanghai University of Traditional Medicine, China (Y.L.).
  • Grandi E; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
  • Nieves-Cintron M; School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, China (A.S.).
  • Xiang YK; Department of Pharmacology, University of California at Davis (B.X., M.L., Y.W., M.Z., S.M., Q.S., Q.W., F.B., J.-P.T., G.R.R., Y.L., A.S., J.L.P., E.G., M.N.-C., Y.K.X.).
Circ Res ; 127(6): 796-810, 2020 08 28.
Article in En | MEDLINE | ID: mdl-32507058
ABSTRACT
RATIONALE Cardiotoxic ß1 adrenergic receptor (ß1AR)-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 ß1AR and organizes a receptor signalosome.

OBJECTIVE:

We aim to elucidate the dynamics of ß1AR-SAP97 signalosome and its potential role in chronic cardiotoxic ß1AR-CaMKII signaling that contributes to development of heart failure. METHODS AND

RESULTS:

The integrity of cardiac ß1AR-SAP97 complex was examined in heart failure. Cardiac-specific deletion of SAP97 was developed to examine ß1AR signaling in aging mice, after chronic adrenergic stimulation, and in pressure overload hypertrophic heart failure. We show that the ß1AR-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 ß1AR 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 ß1AR. Cardiac deletion of GRK5 prevents adrenergic-induced dissociation of ß1AR-SAP97 complex and increases in CaMKII activity in hearts.

CONCLUSIONS:

These data reveal a critical role of SAP97 in maintaining the integrity of cardiac ß1AR 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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Adrenergic, beta-1 / Myocytes, Cardiac / Calcium-Calmodulin-Dependent Protein Kinase Type 2 / G-Protein-Coupled Receptor Kinase 5 / Discs Large Homolog 1 Protein / Heart Failure Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Journal: Circ Res Year: 2020 Type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Receptors, Adrenergic, beta-1 / Myocytes, Cardiac / Calcium-Calmodulin-Dependent Protein Kinase Type 2 / G-Protein-Coupled Receptor Kinase 5 / Discs Large Homolog 1 Protein / Heart Failure Type of study: Prognostic_studies Limits: Animals / Humans / Male Language: En Journal: Circ Res Year: 2020 Type: Article