EP₄ prostanoid receptor coupling to a pertussis toxin-sensitive inhibitory G protein

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 (Gα_s) and, after stimulation with PGE ₂, 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 EP ₄-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 (Gα_i) that can inhibit cAMP-dependent signaling and activate PI3K/ERK-dependent signaling.