ArticleProceedings of the National Academy of Sciences of the United States of America2012
Phosphodiesterases coordinate cAMP propagation induced by two stimulatory G protein-coupled receptors in hearts.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 78 citations in OpenAlex.
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- Cardioprotective Mechanisms of Beta-Blockers in Myocardial Ischemia and Reperfusion: From Molecular Targets to Clinical Implications.International journal of molecular sciences · 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
- Phosphodiesterase in heart and vessels: from physiology to diseases.Physiological reviews · 2024Review
- The βAdvances in pharmacological and pharmaceutical sciences · 2024Review
- PDE4D mediates impaired β-adrenergic receptor signalling in the sinoatrial node in mice with hypertensive heart disease.Cardiovascular research · 2023Article
- The Link between Prostanoids and Cardiovascular Diseases.International journal of molecular sciences · 2023Review
- Probing spatiotemporal PKA activity at the ryanodine receptor and SERCA2a nanodomains in cardomyocytes.Cell communication and signaling : CCS · 2022Article
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- Aquaporin 2 regulation: implications for water balance and polycystic kidney diseases.Nature reviews. Nephrology · 2021Review
- Carvedilol induces biased β1 adrenergic receptor-nitric oxide synthase 3-cyclic guanylyl monophosphate signalling to promote cardiac contractility.Cardiovascular research · 2021Article
- An update of cyclic nucleotide phosphodiesterase as a target for cardiac diseases.Expert opinion on drug discovery · 2021Review
- Intracellular βCirculation research · 2021Article
- The deleterious role of the prostaglandin EAmerican journal of physiology. Heart and circulatory physiology · 2020Article
- PRKAR1A deficiency impedes hypertrophy and reduces heart size.Physiological reports · 2020Article
- Review
- Whole-Cell cAMP and PKA Activity are Epiphenomena, Nanodomain Signaling Matters.Physiology (Bethesda, Md.) · 2019Review
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Inflammation is a significant player in the progression of heart failure and has detrimental effects on cardiac function. Prostaglandin (PG)E2, a major proinflammatory prostanoid in the cardiovascular system, is a potent stimulus in inducing intracellular cAMP but minimally affects cardiac contractile function. Here, we show that the PGE2 stimulation attenuates the adrenergic-induced cardiac contractile response in animal hearts. Stimulation with PGE2 leads to stimulatory G protein (Gs)-dependent production of cAMP. However, the induced cAMP is spatially restricted because of its degradation by phosphodiesterase (PDE)4 and cannot access the intracellular sarcoplasmic reticulum (SR) for increasing calcium signaling and myocyte contraction. Moreover, pretreatment with PGE2 significantly inhibits PKA activities at the SR induced by a β-adrenergic agonist, isoproterenol, and subsequently blocks isoproterenol-induced PKA phosphorylation of phospholamban and contractile responses in myocytes. Further analysis reveals that the PGE2-induced cAMP/PKA is sufficient to phosphorylate and activate PDE4D isoforms, which, in turn, spatially inhibits the diffusion of adrenergic-induced cAMP from the plasma membrane to the SR. Inhibition of PDE4 rescues the adrenergic-induced increase in cAMP/PKA activities at the SR, PKA phosphorylation of phospholamban, and contractile responses in PGE2-pretreated myocytes. Thus, this offers an example that one Gs-coupled receptor is able to inhibit the intracellular signaling transduction initiated by another Gs-coupled receptor via controlling the diffusion of cAMP, presenting a paradigm for G protein-coupled receptor (GPCR) signal transduction. It also provides a mechanism for the integration of signaling initiated by different neurohormonal stimuli, as well as long-term effects of chronically circulating proinflammatory factors in myocardium.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.