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 E(2) (PGE(2)) on Rap1 activation in rheumatoid synovial fibroblasts (RSF). Rap1 was expressed in RSF, and GTP-bound active Rap1 (GTP-Rap1) was rapidly increased by PGE(2). The effect of PGE(2) 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 PGE(2) via cAMP-signaling may play an important role in the articular pathology of rheumatoid arthritis (RA).
Kojima
Fumiaki
F
Division of Rheumatology, Department of Internal Medicine, University of Kentucky, Kentucky Clinic, Lexington, KY 40536-0284, USA.
Kapoor
Mohit
M
Kawai
Shinichi
S
Yang
Lihua
L
Aronoff
David M
DM
Crofford
Leslie J
LJ
D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D051381:Rats; D018078:Receptors, Prostaglandin E / Q000378:metabolism*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000089804:Shelterin Complex; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D013583:Synovial Membrane / Q000378:metabolism / Q000473:pathology*; D034501:Telomere-Binding Proteins / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; C545645:Ptger2 protein, mouse; C545651:Ptger4 protein, mouse; C116122:RAPGEF3 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone