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


RESULTS
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.


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.
Department of Pharmacology, University of California at Davis, Davis, CA 95616, USA.
Qian
Q
Shi
Department of Pharmacology, University of California at Davis, Davis, CA 95616, USA.|Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210001, China.
Minghui
M
Li
INSERM UMR-S 1180, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
Delphine
D
Mika
Department of Pharmacology, Tongji Medical College, Huazhong University of Technology and Sciences, Wuhan 430030, China.
Qin
Q
Fu
Department of Pharmacology, University of California at Davis, Davis, CA 95616, USA.
Sungjin
S
Kim
Department of Pharmacology, University of California at Davis, Davis, CA 95616, USA.
Jason
J
Phan
Department of Pharmacology, University of California at Davis, Davis, CA 95616, USA.
Ao
A
Shen
INSERM UMR-S 1180, Univ. Paris-Sud, Université Paris-Saclay, Châtenay-Malabry, France.
Gregoire
G
Vandecasteele
Department of Pharmacology, University of California at Davis, Davis, CA 95616, USA.|VA Northern California Health care system, Mather, CA 95655, USA.
Yang K
YK
Xiang
D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D006728:Hormones / Q000494:pharmacology*; D008297:Male; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D020239:Receptor Cross-Talk; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000071559:beta-Arrestin 1 / Q000235:genetics / Q000378:metabolism; D000071560:beta-Arrestin 2 / Q000235:genetics / Q000378:metabolism*
C547788:Adrb1 protein, mouse; C547789:Adrb1 protein, rat; C000605255:Arrb1 protein, mouse; C000605258:Arrb2 protein, mouse; C000605257:Arrb2 protein, rat; D006728:Hormones; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C531980:PDE4D protein, mouse; C528468:PDE4D protein, rat
Heterologous desensitization; PKA; PKC; Phosphodiesterase 4; β-Arrestin 2