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 Kevin Xiang

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Aims 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. Methods and results Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists. Activation of G s -coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and G q -coupled α 1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of β 1 AR and β 2 AR at putative protein kinase A (PKA) phosphorylation sites; but activation of G i -coupled α 2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote β 2 AR 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 β 2 AR 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 β 2 AR in a β-arrestin 2 dependent manner without promoting β 2 AR endocytosis. The increased binding between β 2 AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in β 2 AR, 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. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)656-670
Number of pages15
JournalCardiovascular Research
Volume113
Issue number6
DOIs
StatePublished - May 1 2017

Fingerprint

Arrestin
Adrenergic Agents
Adrenergic Receptors
Type 4 Cyclic Nucleotide Phosphodiesterase
Hormones
Phosphorylation
G-Protein-Coupled Receptors
Cyclic AMP-Dependent Protein Kinases
Isoproterenol
Cardiac Myocytes
Cyclic AMP
Prostaglandins G
Proteinase-Activated Receptors
Prostaglandin Receptors
Adrenergic Agonists
Angiotensin Type 1 Receptor
Purinergic P1 Receptors
Ventricular Function
Dopamine Receptors
Endocytosis

Keywords

  • Heterologous desensitization
  • Phosphodiesterase 4
  • PKA
  • PKC
  • β-Arrestin 2

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βaR/arrestin/PDE4 complexes. / Shi, Qian; Li, Minghui; Mika, Delphine; Fu, Qin; Kim, Sungjin; Phan, Jason; Shen, Ao; Vandecasteele, Gregoire; Xiang, Yang Kevin.

In: Cardiovascular Research, Vol. 113, No. 6, 01.05.2017, p. 656-670.

Research output: Contribution to journalArticle

Shi, Qian ; Li, Minghui ; Mika, Delphine ; Fu, Qin ; Kim, Sungjin ; Phan, Jason ; Shen, Ao ; Vandecasteele, Gregoire ; Xiang, Yang Kevin. / Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βaR/arrestin/PDE4 complexes. In: Cardiovascular Research. 2017 ; Vol. 113, No. 6. pp. 656-670.
@article{c918bff8905048d1bb3ddfd4b33f22e7,
title = "Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βaR/arrestin/PDE4 complexes",
abstract = "Aims 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. Methods and results Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists. Activation of G s -coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and G q -coupled α 1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of β 1 AR and β 2 AR at putative protein kinase A (PKA) phosphorylation sites; but activation of G i -coupled α 2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote β 2 AR 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 β 2 AR 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 β 2 AR in a β-arrestin 2 dependent manner without promoting β 2 AR endocytosis. The increased binding between β 2 AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in β 2 AR, 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. Conclusions 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.",
keywords = "Heterologous desensitization, Phosphodiesterase 4, PKA, PKC, β-Arrestin 2",
author = "Qian Shi and Minghui Li and Delphine Mika and Qin Fu and Sungjin Kim and Jason Phan and Ao Shen and Gregoire Vandecasteele and Xiang, {Yang Kevin}",
year = "2017",
month = "5",
day = "1",
doi = "10.1093/cvr/cvx036",
language = "English (US)",
volume = "113",
pages = "656--670",
journal = "Cardiovascular Research",
issn = "0008-6363",
publisher = "Oxford University Press",
number = "6",

}

TY - JOUR

T1 - Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βaR/arrestin/PDE4 complexes

AU - Shi, Qian

AU - Li, Minghui

AU - Mika, Delphine

AU - Fu, Qin

AU - Kim, Sungjin

AU - Phan, Jason

AU - Shen, Ao

AU - Vandecasteele, Gregoire

AU - Xiang, Yang Kevin

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Aims 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. Methods and results Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists. Activation of G s -coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and G q -coupled α 1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of β 1 AR and β 2 AR at putative protein kinase A (PKA) phosphorylation sites; but activation of G i -coupled α 2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote β 2 AR 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 β 2 AR 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 β 2 AR in a β-arrestin 2 dependent manner without promoting β 2 AR endocytosis. The increased binding between β 2 AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in β 2 AR, 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. Conclusions 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.

AB - Aims 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. Methods and results Rat ventricular cardiomyocytes were used to determine heterologous phosphorylation of βARs under a series of GPCR agonists. Activation of G s -coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and G q -coupled α 1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of β 1 AR and β 2 AR at putative protein kinase A (PKA) phosphorylation sites; but activation of G i -coupled α 2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote β 2 AR 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 β 2 AR 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 β 2 AR in a β-arrestin 2 dependent manner without promoting β 2 AR endocytosis. The increased binding between β 2 AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in β 2 AR, 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. Conclusions 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.

KW - Heterologous desensitization

KW - Phosphodiesterase 4

KW - PKA

KW - PKC

KW - β-Arrestin 2

UR - http://www.scopus.com/inward/record.url?scp=85019125857&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85019125857&partnerID=8YFLogxK

U2 - 10.1093/cvr/cvx036

DO - 10.1093/cvr/cvx036

M3 - Article

C2 - 28339772

AN - SCOPUS:85019125857

VL - 113

SP - 656

EP - 670

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

IS - 6

ER -