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Accelerated Communication

EP₄ Prostanoid Receptor Coupling to a Pertussis Toxin-Sensitive Inhibitory G Protein

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona

The EP₂ and EP₄ prostanoid receptor subtypes are G-protein-coupled receptors for prostaglandin E₂ (PGE₂). Both receptor subtypes are known to couple to the stimulatory guanine nucleotide binding protein (G_s) and, after stimulation with PGE₂, can increase the formation of intracellular cAMP. In addition, PGE₂ stimulation of the EP₄ receptor can activate phosphatidylinositol 3-kinase (PI3K) leading to phosphorylation of the extracellular signal-regulated kinases (ERKs) and induction of early growth response factor-1 (EGR-1) (J Biol Chem 278: 12151–12156, 2003). We now report that the PGE₂-mediated phosphorylation of the ERKs and induction of EGR-1 can be blocked by pretreatment of EP₄-expressing cells with pertussis toxin (PTX). Furthermore, pretreatment with PTX increased the amount of PGE₂-stimulated intracellular cAMP formation in EP₄-expressing cells but not in EP₂-expressing cells. These data indicate that the EP₄ prostanoid receptor subtype, but not the EP₂, couples to a PTX-sensitive inhibitory G-protein (G_i) that can inhibit cAMP-dependent signaling and activate PI3K/ERK-dependent signaling.

Address correspondence to: John W. Regan, Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ 85721-0207. E-mail: regan{at}pharmacy.arizona.edu

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