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Palmitoylation regulates intracellular trafficking of ?2 adrenergic receptor/arrestin/phosphodiesterase 4D complexes in cardiomyocytes.

ABSTRACT: ?(2) adrenergic receptor (?(2)AR) is a prototypical G-protein coupled receptor that stimulates the classic cAMP-protein kinase A (PKA) signaling pathway. Recent studies indicate that the cAMP-PKA activities are spatiotemporally regulated in part due to dynamic association of ?(2)AR with phosphodiesterase 4D (PDE4D), a group of cAMP degradation enzymes. Here, we demonstrate that in cardiomyocytes, palmitoylation of ?(2)AR, the covalent acylation of cysteine residue 341, plays a critical role in shaping subcellular cAMP-PKA activities in cardiomyocytes via regulating ?(2)AR association with arrestin/PDE4D. Replacing cysteine 341 on ?(2)AR with alanine (C341A) leads to an impaired binding to ? arrestin 2. Surprisingly, the C341A mutant is able to internalize via an arrestin-independent pathway at saturated concentration of agonist stimulation; the internalization becomes caveolae-dependent and requires dynamin GTPase. However, the impaired binding to ? arrestin 2 also leads to an impaired recruitment of PDE4D to the C341A mutant. Thus, the mutant C341A ?(2)AR is transported alone from the plasma membrane to the endosome without recruiting PDE4D. This alteration leads to an enhanced cytoplasmic cAMP signal for PKA activation under ?(2)AR stimulation. Functionally, Mutation of the C341 residue or inhibition of palmitoylation modification of ?(2)AR enhances the receptor-induced PKA activities in the cytoplasm and increases in myocyte contraction rate. Our data reveal a novel function of palmitoylation in shaping subcellular cAMP-PKA signaling in cardiomyocytes via modulating the recruitment of ? arrestin 2-PDE4D complexes to the agonist-stimulated ?(2)AR.

SUBMITTER: Liu R

PROVIDER: S-EPMC3415400 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Palmitoylation regulates intracellular trafficking of β2 adrenergic receptor/arrestin/phosphodiesterase 4D complexes in cardiomyocytes.

Liu Ruijie R Wang Dayong D Shi Qian Q Fu Qin Q Hizon Steven S Xiang Yang K YK

PloS one 20120809 8

β(2) adrenergic receptor (β(2)AR) is a prototypical G-protein coupled receptor that stimulates the classic cAMP-protein kinase A (PKA) signaling pathway. Recent studies indicate that the cAMP-PKA activities are spatiotemporally regulated in part due to dynamic association of β(2)AR with phosphodiesterase 4D (PDE4D), a group of cAMP degradation enzymes. Here, we demonstrate that in cardiomyocytes, palmitoylation of β(2)AR, the covalent acylation of cysteine residue 341, plays a critical role in s ...[more]

PMID: 22912718

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Project description:AimsCardiac ?-adrenergic receptor (?AR) 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 ?ARs and a set of G-protein coupled receptors (GPCRs) activated by hormones/agonists.Methods and resultsRat ventricular cardiomyocytes were used to determine heterologous phosphorylation of ?ARs under a series of GPCR agonists. Activation of Gs-coupled dopamine receptor, adenosine receptor, relaxin receptor and prostaglandin E2 receptor, and Gq-coupled ?1 adrenergic receptor and angiotensin II type 1 receptor promotes phosphorylation of ?1AR and ?2AR at putative protein kinase A (PKA) phosphorylation sites; but activation of Gi-coupled ?2 adrenergic receptor and activation of protease-activated receptor does not. The GPCR agonists that promote ?2AR phosphorylation effectively inhibit ?AR agonist isoproterenol-induced PKA phosphorylation of phospholamban and contractile function in ventricular cardiomyocytes. Heterologous GPCR stimuli have minimal to small effect on isoproterenol-induced ?2AR 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 ?2AR in a ?-arrestin 2 dependent manner without promoting ?2AR endocytosis. The increased binding between ?2AR and PDE4D effectively hydrolyzes cAMP signal generated by subsequent stimulation with isoproterenol. Mutation of PKA phosphorylation sites in ?2AR, inhibition of PDE4, or genetic ablation of PDE4D or ?-arrestin 2 abolishes this heterologous inhibitory effect. Ablation of ?-arrestin 2 or PDE4D gene also rescues ?-adrenergic stimuli-induced myocyte contractile function.ConclusionsThese data reveal essential roles of ?-arrestin 2 and PDE4D in a common mechanism for heterologous desensitization of cardiac ?ARs under hormonal stimulation, which is associated with impaired cardiac function during the development of pathophysiological conditions.

Dataset Information

Palmitoylation regulates intracellular trafficking of ?2 adrenergic receptor/arrestin/phosphodiesterase 4D complexes in cardiomyocytes.

Publications

Palmitoylation regulates intracellular trafficking of β2 adrenergic receptor/arrestin/phosphodiesterase 4D complexes in cardiomyocytes.

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