Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes

Qian Shi; Minghui Li; Delphine Mika; Qin Fu; Sungjin Kim; Jason Phan; Ao Shen; Gregoire Vandecasteele; Yang K Xiang

doi:10.1093/cvr/cvx036

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Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes

Journal article

Open access

Peer reviewed

Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes

Qian Shi, Minghui Li, Delphine Mika, Qin Fu, Sungjin Kim, Jason Phan, Ao Shen, Gregoire Vandecasteele and Yang K Xiang

Cardiovascular research, Vol.113(6), pp.656-670

05/01/2017

DOI: 10.1093/cvr/cvx036

PMCID: PMC5852637

PMID: 28339772

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Abstract

Cardiac β-adrenergic receptor (βAR) signalling is susceptible to heterologous desensitization by different neurohormonal stimuli in clinical conditions associated with heart failure. We aim to examine the underlying mechanism of cross talk between βARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists. Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists. Activation of Gs-coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and Gq-coupled α1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of β1AR and β2AR at putative protein kinase A (PKA) phosphorylation sites; but activation of Gi-coupled α2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote β2AR phosphorylation effectively inhibit βAR agonist isoproterenol-induced PKA phosphorylation of phospholamban and contractile function in ventricular cardiomyocytes. Heterologous GPCR stimuli have minimal to small effect on isoproterenol-induced β2AR activation and G-protein coupling for cyclic adenosine monophosphate (cAMP) production. However, these GPCR stimuli significantly promote phosphorylation of phosphodiesterase 4D (PDE4D), and recruit PDE4D to the phosphorylated β2AR in a β-arrestin 2 dependent manner without promoting β2AR endocytosis. The increased binding between β2AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in β2AR, inhibition of PDE4, or genetic ablation of PDE4D or β-arrestin 2 abolishes this heterologous inhibitory effect. Ablation of β-arrestin 2 or PDE4D gene also rescues β-adrenergic stimuli-induced myocyte contractile function. These data reveal essential roles of β-arrestin 2 and PDE4D in a common mechanism for heterologous desensitization of cardiac βARs under hormonal stimulation, which is associated with impaired cardiac function during the development of pathophysiological conditions.

Animals

beta-Arrestin 1 - genetics

beta-Arrestin 1 - metabolism

beta-Arrestin 2 - genetics

beta-Arrestin 2 - metabolism

Cells, Cultured

Cyclic AMP-Dependent Protein Kinases - metabolism

Cyclic Nucleotide Phosphodiesterases, Type 4 - genetics

Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism

Hormones - pharmacology

Male

Mice, Knockout

Myocardial Contraction - drug effects

Myocytes, Cardiac - drug effects

Myocytes, Cardiac - metabolism

Phosphorylation

Protein Kinase C - metabolism

Rats

Receptor Cross-Talk

Receptors, Adrenergic, beta-1 - drug effects

Receptors, Adrenergic, beta-1 - genetics

Receptors, Adrenergic, beta-1 - metabolism

Receptors, Adrenergic, beta-2 - drug effects

Receptors, Adrenergic, beta-2 - genetics

Receptors, Adrenergic, beta-2 - metabolism

Signal Transduction - drug effects

Time Factors

Details

Title: Subtitle: Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes
Creators: Qian Shi - University of California, Davis
Minghui Li - Nanjing Medical University
Delphine Mika - Université Paris-Saclay
Qin Fu - Department of Pharmacology, Tongji Medical College, Huazhong University of Technology and Sciences, Wuhan 430030, China;
Sungjin Kim - University of California, Davis
Jason Phan - University of California, Davis
Ao Shen - University of California, Davis
Gregoire Vandecasteele - Université Paris-Saclay
Yang K Xiang - University of California, Davis
Resource Type: Journal article
Publication Details: Cardiovascular research, Vol.113(6), pp.656-670
DOI: 10.1093/cvr/cvx036
PMID: 28339772
PMCID: PMC5852637
ISSN: 0008-6363
eISSN: 1755-3245
Grant note: R01 HL127764 / NHLBI NIH HHS R01 HL112413 / NHLBI NIH HHS
Language: English
Date published: 05/01/2017
Academic Unit: Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984359920102771

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