title: Phosphodiesterases coordinate cAMP propagation induced by two stimulatory G protein-coupled receptors in hearts.
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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, IL 61801, USA.
authors.forename: Shubai
authors.initials: S
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Sungjin
authors.initials: S
authors.lastname: Kim
authors.forename: Qin
authors.initials: Q
authors.lastname: Fu
authors.forename: Dippal
authors.initials: D
authors.lastname: Parikh
authors.forename: Bharat
authors.initials: B
authors.lastname: Sridhar
authors.forename: Qian
authors.initials: Q
authors.lastname: Shi
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Zhang
authors.forename: Yinzheng
authors.initials: Y
authors.lastname: Guan
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Chen
authors.forename: Yang K
authors.initials: YK
authors.lastname: Xiang
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D011943:Receptors, Adrenergic, beta; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D015232:Dinoprostone; D007545:Isoproterenol