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 Gi- or Gq-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 Gs-coupled receptors. In this report, we used COS-7 cells transfected with the dopamine D1 receptor (D1R) to illustrate the signaling mechanism for Gs-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 Gbetagamma, 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 Gs-coupled D1R weakly potentiated the JNK activation induced by the Gi-coupled opioid receptor-like receptor, but it exhibited a significant inhibitory effect on the kinase activity triggered by the Gq-coupled gastrin-releasing peptide-preferring bombesin receptor (GRPR). Administration of Spadenosine-3',5'-cyclic monophosphorothioate triethylamine (a cAMP analog that mimics the Gs/cAMP signal) also suppressed the JNK activation mediated by Gq-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 Gs-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.
Chan
Anthony S L
AS
Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong.
Wong
Yung H
YH
D000818:Animals; D019556:COS Cells; D020013:Calcium Signaling; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000502:physiology; D004789:Enzyme Activation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D018004:Receptors, Bombesin / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D015398:Signal Transduction
D018004:Receptors, Bombesin; D017447:Receptors, Dopamine D1; D000242:Cyclic AMP; D048031:JNK Mitogen-Activated Protein Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs