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Background Signaling pathways that regulate the production of cytokines and destructive enzymes have been implicated in rheumatoid arthritis (RA) pathogenesis.There are co-relations between signaling pathways.The aim of this study was to investigate interactions and cross-talks between MEK1/2-extracellular signal-related kinase (ERK1/2)signaling and G protein-couple signaling in synoviocytes of collagen-induced arthritis (CIA) rats by the stimulation of interleukin-1 (IL-1),U0126,isoprenaline hydrochloride and aminophyline respectively.Methods Twenty Sprague-Dawley (SD) rats were induced by chicken type Ⅱ collagen.Synoviocytes of CIA rats were isolated and cultured.The expressions of Gi,phosphorylated MEK1/2 (p-MEK1/2) and phosphorylated ERK1/2 (p-ERK1/2) were detected by West blotting.cAMP level and protein kinase A (PKA) activity were measured by radioimmunoassay and kinase-glo(R) luminescent kinase assay respectively.Results There was remarkable inflammation in CIA rats accompanied by swelling paws,hyperplastic synovium,pannus and cartilage erosion,cAMP level and PKA activity of synoviocytes decreased.Gi,p-ERK1/2 and p-MEK1/2 increased,rIL-1α improved the expression of Gi,p-ERK1/2 and p-MEK1/2,cAMP and PKA increased with stimulation of rIL-1α.U0126 inhibited Gi,cAMP and PKA of synoviocytes stimulated by rIL-1α.Isoprenaline hydrochloride enhanced Gi,cAMP and PKA,but had no effects on p-MEK1/2 and p-ERK1/2.Aminophyline increased cAMP and PKA,but inhibited p-MEK1/2 and p-ERK1/2.Conclusions Mitogen-activated protein kinases (MAPKs) and G protein-couple signaling are associated with synovitis.There are cross talks between MAPKs and G protein-couple signaling.The two signaling pathways represent potential therapeutic targets for RA.