ArticleThe Journal of biological chemistry2014
A long lasting β1 adrenergic receptor stimulation of cAMP/protein kinase A (PKA) signal in cardiac myocytes.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 36 citations in OpenAlex.
- The beta1-adrenergic receptor in the heart.Cell death discovery · 2025Review
- Inhibition of the upregulated phosphodiesterase 4D isoforms improves SERCA2a function in diabetic cardiomyopathy.British journal of pharmacology · 2025Article
- Differential Downregulation of βJournal of the American Heart Association · 2024Article
- Adrenoceptor Desensitization: Current Understanding of Mechanisms.Pharmacological reviews · 2024Review
- Phosphodiesterase in heart and vessels: from physiology to diseases.Physiological reviews · 2024Review
- Targeting neuro-immune systems to achieve cardiac tissue repair following myocardial infarction: A review of therapeutic approaches from in-vivo preclinical to clinical studies.Pharmacology & therapeutics · 2023Review
- Review
- GRK5 Controls SAP97-Dependent Cardiotoxic βCirculation research · 2020Article
- Carvedilol Prevents Redox Inactivation of Cardiomyocyte ΒJACC. Basic to translational science · 2018Article
- Decreased autophagy induced by βCell death & disease · 2018Article
- Barcoding of GPCR trafficking and signaling through the various trafficking roadmaps by compartmentalized signaling networks.Cellular signalling · 2017Review
- Insulin and β Adrenergic Receptor Signaling: Crosstalk in Heart.Trends in endocrinology and metabolism: TEM · 2017Review
- Heterologous desensitization of cardiac β-adrenergic signal via hormone-induced βAR/arrestin/PDE4 complexes.Cardiovascular research · 2017Article
- Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure.Circulation research · 2016Article
- BRAF kinase inhibitor exerts anti-tumor activity against breast cancer cells via inhibition of FGFR2.American journal of cancer research · 2016Article
- Mouse models for the study of postnatal cardiac hypertrophy.International journal of cardiology. Heart & vasculature · 2015Article
- Principles of Ocular Pharmacology.Handbook of experimental pharmacologyArticle
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
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 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 t½ of 3.9 h) in cardiac myocytes. However, the β1AR-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.
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