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

Ruijie Liu, Dayong Wang, Qian Shi, Qin Fu, Steven Hizon, Yang Kevin Xiang

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

β2 adrenergic receptor (β2AR) 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 β2AR with phosphodiesterase 4D (PDE4D), a group of cAMP degradation enzymes. Here, we demonstrate that in cardiomyocytes, palmitoylation of β2AR, the covalent acylation of cysteine residue 341, plays a critical role in shaping subcellular cAMP-PKA activities in cardiomyocytes via regulating β2AR association with arrestin/PDE4D. Replacing cysteine 341 on β2AR with alanine (C341A) leads to an impaired binding to β 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 β arrestin 2 also leads to an impaired recruitment of PDE4D to the C341A mutant. Thus, the mutant C341A β2AR 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 β2AR stimulation. Functionally, Mutation of the C341 residue or inhibition of palmitoylation modification of β2AR 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 β arrestin 2-PDE4D complexes to the agonist-stimulated β2AR.

Original languageEnglish (US)
Article numbere42658
JournalPLoS One
Volume7
Issue number8
DOIs
StatePublished - Aug 9 2012

Fingerprint

arrestins
Type 4 Cyclic Nucleotide Phosphodiesterase
Lipoylation
Arrestin
adrenergic receptors
Cardiac Myocytes
Adrenergic Receptors
cAMP-dependent protein kinase
Cyclic AMP-Dependent Protein Kinases
mutants
agonists
Cysteine
cysteine
Association reactions
Dynamins
cardiomyocytes
palmitoylation
Caveolae
Acylation
acylation

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Palmitoylation regulates intracellular trafficking of β2 adrenergic receptor/arrestin/phosphodiesterase 4D complexes in cardiomyocytes. / Liu, Ruijie; Wang, Dayong; Shi, Qian; Fu, Qin; Hizon, Steven; Xiang, Yang Kevin.

In: PLoS One, Vol. 7, No. 8, e42658, 09.08.2012.

Research output: Contribution to journalArticle

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