Gq-mediated activation of c-Jun N-terminal kinase by the gastrin-releasing peptide-preferring bombesin receptor is inhibited upon costimulation of the Gs-coupled dopamine D1 receptor in COS-7 cells

G protein-coupled receptors (GPCRs) of G(i)- or G(q)-coupling specificity are effectively linked to activation of the c-Jun N-terminal kinase (JNK) cascade. However, little is known with regard to the regulation of JNK by G(s)-coupled receptors. In this report, we used COS-7 cells transfected with the dopamine D-1 receptor (D1R) to illustrate the signaling mechanism for G(s)-mediated JNK activation. Stimulation of D1R triggered a weak but significant elevation of JNK activity in a time- and dose-dependent manner. This D1R-mediated JNK activation required the participation of G beta gamma, Src- like kinases, and small GTPases, whereas disruptions of cAMP-, phosphoinositide-3-kinase-, and epidermal growth factor receptor-mediated signaling had no effect. Costimulation of D1R with GPCRs of other coupling specificities resulted in differential activation profiles of JNK. Activation of G(s)-coupled D1R weakly potentiated the JNK activation induced by the G(i)-coupled opioid receptor-like receptor, but it exhibited a significant inhibitory effect on the kinase activity triggered by the G(q)-coupled gastrin-releasing peptide-preferring bombesin receptor (GRPR). Administration of Sp-adenosine-3', 5'-cyclic monophosphorothioate triethylamine ( a cAMP analog that mimics the G(s)/cAMP signal) also suppressed the JNK activation mediated by G(q)-coupled GRPR, as well as the Ca2+-induced kinase activation upon thapsigargin treatment. Moreover, the Ca2+ signal from GRPR synergistically potentiated the D1R-triggered cAMP elevation when the two receptors were stimulated simultaneously. Taken together, our results demonstrated that stimulation of G(s)-coupled receptors in COS-7 cells not only enhanced the JNK activity, but also exhibited a "tuning" effect on the kinase activation mediated by GPCRs of other coupling specificities.