EP(4) prostanoid receptor coupling to a pertussis toxin-sensitive inhibitory G protein.

The EP(2) and EP(4) prostanoid receptor subtypes are G-protein-coupled receptors for prostaglandin E(2) (PGE(2)). Both receptor subtypes are known to couple to the stimulatory guanine nucleotide binding protein (Galpha(s)) and, after stimulation with PGE(2), can increase the formation of intracellular cAMP. In addition, PGE(2) stimulation of the EP(4) 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). We now report that the PGE(2)-mediated phosphorylation of the ERKs and induction of EGR-1 can be blocked by pretreatment of EP(4)-expressing cells with pertussis toxin (PTX). Furthermore, pretreatment with PTX increased the amount of PGE(2)-stimulated intracellular cAMP formation in EP(4)-expressing cells but not in EP(2)-expressing cells. These data indicate that the EP(4) prostanoid receptor subtype, but not the EP(2), couples to a PTX-sensitive inhibitory G-protein (Galpha(i)) that can inhibit cAMP-dependent signaling and activate PI3K/ERK-dependent signaling.