Phosphodiesterases coordinate cAMP propagation induced by two stimulatory G protein-coupled receptors in hearts

Shubai Liu, Ying Li, Sungjin Kim, Qin Fu, Dippal Parikh, Bharat Sridhar, Qian Shi, Xiaoying Zhang, Yinzheng Guan, Xiongwen Chen, Yang Kevin Xiang

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)6578-6583
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number17
DOIs
StatePublished - Apr 24 2012

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Phosphoric Diester Hydrolases
G-Protein-Coupled Receptors
Dinoprostone
Sarcoplasmic Reticulum
Adrenergic Agents
Muscle Cells
Isoproterenol
Gs GTP-Binding Protein alpha Subunits
Phosphorylation
Type 4 Cyclic Nucleotide Phosphodiesterase
Adrenergic Agonists
Calcium Signaling
Cardiovascular System
Prostaglandins
Signal Transduction
Myocardium
Protein Isoforms
Heart Failure
Cell Membrane
Inflammation

Keywords

  • Cross-talk
  • FRET
  • Subcellular diffusion

ASJC Scopus subject areas

  • General

Cite this

Phosphodiesterases coordinate cAMP propagation induced by two stimulatory G protein-coupled receptors in hearts. / Liu, Shubai; Li, Ying; Kim, Sungjin; Fu, Qin; Parikh, Dippal; Sridhar, Bharat; Shi, Qian; Zhang, Xiaoying; Guan, Yinzheng; Chen, Xiongwen; Xiang, Yang Kevin.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 17, 24.04.2012, p. 6578-6583.

Research output: Contribution to journalArticle

Liu, Shubai ; Li, Ying ; Kim, Sungjin ; Fu, Qin ; Parikh, Dippal ; Sridhar, Bharat ; Shi, Qian ; Zhang, Xiaoying ; Guan, Yinzheng ; Chen, Xiongwen ; Xiang, Yang Kevin. / Phosphodiesterases coordinate cAMP propagation induced by two stimulatory G protein-coupled receptors in hearts. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 17. pp. 6578-6583.
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AU - Parikh, Dippal

AU - Sridhar, Bharat

AU - Shi, Qian

AU - Zhang, Xiaoying

AU - Guan, Yinzheng

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AU - Xiang, Yang Kevin

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AB - 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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