Journal article
Palmitoylation Regulates Intracellular Trafficking of beta(2) Adrenergic Receptor/Arrestin/Phosphodiesterase 4D Complexes in Cardiomyocytes
PloS one, Vol.7(8), e42658
08/09/2012
DOI: 10.1371/journal.pone.0042658
PMCID: PMC3415400
PMID: 22912718
Abstract
beta(2) adrenergic receptor (beta(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 beta(2)AR with phosphodiesterase 4D (PDE4D), a group of cAMP degradation enzymes. Here, we demonstrate that in cardiomyocytes, palmitoylation of beta(2)AR, the covalent acylation of cysteine residue 341, plays a critical role in shaping subcellular cAMP-PKA activities in cardiomyocytes via regulating beta(2)AR association with arrestin/PDE4D. Replacing cysteine 341 on beta(2)AR with alanine (C341A) leads to an impaired binding to beta 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 beta arrestin 2 also leads to an impaired recruitment of PDE4D to the C341A mutant. Thus, the mutant C341A beta(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 beta(2)AR stimulation. Functionally, Mutation of the C341 residue or inhibition of palmitoylation modification of beta(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 b arrestin 2-PDE4D complexes to the agonist-stimulated beta(2)AR.
Details
- Title: Subtitle
- Palmitoylation Regulates Intracellular Trafficking of beta(2) Adrenergic Receptor/Arrestin/Phosphodiesterase 4D Complexes in Cardiomyocytes
- Creators
- Ruijie Liu - Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL USADayong Wang - University of Illinois Urbana-ChampaignQian Shi - University of Illinois Urbana-ChampaignQin Fu - University of Illinois Urbana-ChampaignSteven Hizon - University of Illinois Urbana-ChampaignYang K. Xiang - University of California, Davis
- Resource Type
- Journal article
- Publication Details
- PloS one, Vol.7(8), e42658
- DOI
- 10.1371/journal.pone.0042658
- PMID
- 22912718
- PMCID
- PMC3415400
- NLM abbreviation
- PLoS One
- ISSN
- 1932-6203
- eISSN
- 1932-6203
- Publisher
- Public Library Science
- Number of pages
- 13
- Grant note
- HL082646 / NIH grant; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL082846 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) 0635331N / American Heart Association grant; American Heart Association
- Language
- English
- Date published
- 08/09/2012
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359923102771
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