Journal article
A Long Lasting beta(1) Adrenergic Receptor Stimulation of cAMP/Protein Kinase A (PKA) Signal in Cardiac Myocytes
The Journal of biological chemistry, Vol.289(21), pp.14771-14781
05/23/2014
DOI: 10.1074/jbc.M113.542589
PMCID: PMC4031532
PMID: 24713698
Abstract
Small-molecule, ligand-activated G protein-coupled receptors are generally thought to be rapidly desensitized within a period of minutes through receptor phosphorylation and internalization after repeated or prolonged stimulation. This transient G protein-coupled receptor activation remains at odds with many observed long-lasting cellular and physiological responses. Here, using live cell imaging of cAMP with a FRET-based biosensor and myocyte contraction assay, we show that the catecholamine-activated beta(1) adrenergic receptor (beta(1)AR) continuously stimulates second messenger cAMP synthesis in primary cardiac myocytes and neurons, which lasts for more than 8 h (a decay t(1/2) of 3.9 h) in cardiac myocytes. However, the beta(1)AR-induced cAMP signal is counterbalanced and masked by the receptor-bound phosphodiesterase (PDE) 4D8-dependent cAMP hydrolysis. Inhibition of PDE4 activity recovers the receptor-induced cAMP signal and promotes contractile response in mouse hearts during extended periods of agonist stimulation. beta(1)AR associates with PDE4D8 through the receptor C-terminal PDZ motif-dependent binding to synaptic-associated protein 97 (SAP97). Knockdown of SAP97 or mutation of the beta(1)AR PDZ motif disrupts the complex and promotes sustained agonist-induced cAMP activity, PKA phosphorylation, and cardiac myocyte contraction response. Together, these findings unveil a long lasting adrenergic signal in neurons and myocytes under prolonged stimulation and an underappreciated role of PDE that is essential in classic receptor signaling desensitization and in maintaining a long lasting cAMP equilibrium for ligand-induced physiological response.
Details
- Title: Subtitle
- A Long Lasting beta(1) Adrenergic Receptor Stimulation of cAMP/Protein Kinase A (PKA) Signal in Cardiac Myocytes
- Creators
- Qin Fu - University of Illinois Urbana-ChampaignSungjin Kim - University of California, DavisDagoberto Soto - University of Illinois Urbana-ChampaignVania De Arcangelis - University of Illinois Urbana-ChampaignLisa DiPilato - Johns Hopkins UniversityShubai Liu - University of Illinois Urbana-ChampaignBing Xu - University of California, DavisQian Shi - University of Illinois Urbana-ChampaignJin Zhang - Johns Hopkins UniversityYang K. Xiang - University of California, Davis
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.289(21), pp.14771-14781
- DOI
- 10.1074/jbc.M113.542589
- PMID
- 24713698
- PMCID
- PMC4031532
- NLM abbreviation
- J Biol Chem
- eISSN
- 1083-351X
- Publisher
- Amer Soc Biochemistry Molecular Biology Inc
- Number of pages
- 11
- Grant note
- 0635331N / American Heart Association R01DK073368 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) DK073368; HL082646 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 05/23/2014
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359572302771
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