Prostaglandin E2 activates Rap1 via EP2/EP4 receptors and cAMP-signaling in rheumatoid synovial fibroblasts: Involvement of Epac1 and PKA

The small GTPase Rap1 is implicated in a variety of cellar functions. In this study, we investigated the effect of prostaglandin E2 (PGE2) on Rap1 activation in rheumatoid synovial fibroblasts (RSF). Rap1 was expressed in RSF, and GTP-bound active Rap1 (GTP-Rap1) was rapidly increased by PGE2. The effect of PGE2 was mimicked by an EP2 receptor agonist, an EP4 agonist and a cAMP-elevating agent forskolin with association to the increase of cAMP, but not by an EP1 or an EP3 agonist. RSF expressed the downstream signaling partners of cAMP, exchange protein directly activated by cAMP (Epac1) and protein kinase A (PKA). Both 8-pCPT-2-O-Me-cAMP (an Epac-specific cAMP analog) and 6-Bnz-cAMP (a PKA-specific cAMP analog) activated Rap1 in RSF. Activation of Rap1 by PGE2 via cAMP-signaling may play an important role in the articular pathology of rheumatoid arthritis (RA).