A long lasting β1 adrenergic receptor stimulation of cAMP/Protein kinase A (PKA) signal in cardiac myocytes

Qin Fu, Sungjin Kim, Dagoberto Soto, Vania De Arcangelis, Lisa DiPilato, Shubai Liu, Bing Xu, Qian Shi, Jin Zhang, Yang Kevin Xiang

Research output: Contribution to journalArticle

15 Scopus citations

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 FRETbased biosensor and myocyte contraction assay, we show that the catecholamine-activated β1 adrenergic receptor ( β1AR) continuously stimulates second messenger cAMP synthesis in primary cardiac myocytes and neurons, which lasts for more than 8 h (a decay t1/2 of 3.9 h) in cardiac myocytes. However, the β 1AR-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. β1AR 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 β1AR 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.

Original languageEnglish (US)
Pages (from-to)14771-14781
Number of pages11
JournalJournal of Biological Chemistry
Volume289
Issue number21
DOIs
StatePublished - 2014

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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    Fu, Q., Kim, S., Soto, D., De Arcangelis, V., DiPilato, L., Liu, S., Xu, B., Shi, Q., Zhang, J., & Xiang, Y. K. (2014). A long lasting β1 adrenergic receptor stimulation of cAMP/Protein kinase A (PKA) signal in cardiac myocytes. Journal of Biological Chemistry, 289(21), 14771-14781. https://doi.org/10.1074/jbc.M113.542589