Received for publication May 9, 2005.
Revised July 8, 2005.
Accepted for publication July 28, 2005.

G_q-mediated activation of JNK by the GRP receptor is inhibited upon co-stimulation of the G_s-coupled dopamine D₁ receptor in Cos-7 cells

Abstract

G protein-coupled receptors (GPCRs) of G_i or G_q coupling specificity are effectively linked to activation of the JNK cascade. However, little is known with regard to the regulation of JNK by G_s-coupled receptors. In this report, we utilized Cos-7 cells transfected with the dopamine D₁ 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, Src-like kinases and small GTPases, while disruptions of cAMP-, PI3K-, and EGFR-mediated signaling had no effect. Co-stimulation 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 (ORL₁R), but 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-cAMPS (a cAMP analogue which 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 simultaneously stimulated. 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.

Key words: Gs family, Gq/11 family, Src and other nonreceptor tyrosine kinases, Ras, Cdc42, rho, rac, other small G proteins, Jun Kinase

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