Activation of mitogen-activated protein kinase by the human prostaglandin EP_3A receptor

Mitogen-activated protein (MAP) kinases are involved with cellular proliferation, and while the traditional activators of these kinases have been the growth factor receptors, recent data indicate that G-protein coupled receptors which inhibit adenylyl cyclase can activate MAP kinases as well. We have recently cloned an alternative splice variant of a human receptor for prostaglandin E₂ (PGE₂) which inhibits adenylyl cyclase and as been defined as the EP_3A (Brit. J. Pharmacol. 112:377, 1994). In the present study the ability of this receptor to activate MAP kinase was examined. In crude lysates of COS-7 cells transfected with the human EP_3A, 1 μM PGE₂ stimicrolated MAP kinase activity ∼1.3-fold with an EC₅₀ of ∼6 nM. Ion exchange chromatography followed by immicronoblot analysis showed that the stimicrolation of MAP kinase activity co-fractionated with immicronoreactive MAP-2 kinase (ERK1). This activation of MAP kinase activity by the EP_3A receptor may explain the proliferative actions of PGE₂ in some tissues.