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Edited by Robert J. Lefkowitz, Duke University Medical Center/Howard Hughes Medical Institute, Durham, NC, and approved March 15, 2012 (received for review October 29, 2011)
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.
Footnotes
↵1S.L. and Y.L. contributed equally to this work.
- ↵2To whom correspondence may be addressed. E-mail: xchen001{at}temple.edu or kevinyx{at}illinois.edu.
↵3Present address: Department of Pharmacology, University of California, Davis, CA 95616.
Author contributions: S.L., Y.L., Q.F., X.C., and Y.K.X. designed research; S.L., Y.L., S.K., Q.F., D.P., B.S., Q.S., X.Z., and Y.G. performed research; S.L., Q.F., D.P., Q.S., X.C., and Y.K.X. analyzed data; and X.C. and Y.K.X. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1117862109/-/DCSupplemental.
Cross-talk between Gs-coupled receptors
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