Abstract

We investigated the effects of D₁ dopamine receptor stimulation on the activation of mitogen-activated protein kinases (MAPKs) in SK-N-MC human neuroblastoma cells. We found that the D₁ dopamine receptor agonist SKF38393 induced similar time- and dose-related activation of p38 MAPK and c-Jun amino-terminal kinase (JNK), whereas extracellular signal-regulated kinase activity was not affected by D₁ dopamine receptor stimulation. Maximal stimulation of p38 MAPK and JNK was observed after a 15-min incubation with 100 μm SKF38393. In contrast, 10 μmquinpirole, a D₂ dopamine receptor agonist, did not activate p38 MAPK or JNK. Treatment of cells with 10 μmSCH23390, a D₁ dopamine receptor antagonist, significantly inhibited the activation of both kinases by SKF38393. These results indicate that activation of the p38 MAPK and JNK signaling pathways is mediated by dopamine D₁ receptors in SK-N-MC neuroblastoma cells. Furthermore, dibutyryl-cAMP mimicked SKF38393-mediated stimulation of p38 MAPK and JNK. Inhibition of protein kinase A by 1 μm H-89 or 10 μm adenosine 3′,5′-cyclic monophosphothioate (Rp-isomer, triethylammonium salt) markedly attenuated the activation of p38 MAPK and JNK. Conversely, the selective protein kinase C inhibitor calphostin C did not block D₁ dopamine receptor-stimulated activation of p38 MAPK and JNK. These results demonstrate, for the first time, that the G_s-coupled D₁ dopamine receptor activates the p38 MAPK and JNK signaling pathways by a protein kinase A-dependent mechanism.