D-1 DOPAMINE-RECEPTOR AGONISTS MEDIATE ACTIVATION OF P38 MITOGEN-ACTIVATED PROTEIN-KINASE AND C-JUN AMINO-TERMINAL KINASE BY A PROTEIN-KINASE-A DEPENDENT MECHANISM IN SK-N-MC HUMAN NEUROBLASTOMA-CELLS

We investigated the effects of D-1 dopamine receptor stimulation on th e activation of mitogen-activated protein kinases (MAPKs) in SK-N-MC h uman neuroblastoma cells. We found that the D-1 dopamine receptor agon ist SKF38393 induced similar time- and dose-related activation of p38 MARK and c-Jun amino-terminal kinase (JNK), whereas extracellular sign al-regulated kinase activity was not affected by D-1 dopamine receptor stimulation. Maximal stimulation of p38 MARK and JNK was observed aft er a 15-min incubation with 100 mu M SKF38393. In contrast, 10 mu M qu inpirole, a D-2 dopamine receptor agonist, did not activate p38 MARK o r JNK. Treatment of cells with 10 mu M SCH23390, a D-1 dopamine recept or antagonist, significantly inhibited the activation of both kinases by SKF38393. These results indicate that activation of the p38 MARK an d JNK signaling pathways is mediated by dopamine D-1 receptors in SK-N -MC neuroblastoma cells. Furthermore, dibutyryl-cAMP mimicked SKF38393 -mediated stimulation of p38 MARK and JNK. Inhibition of protein kinas e A by 1 mu M H-89 or 10 mu M adenosine 3',5'-cyclic monophosphothioat e (Rp-isomer, triethylammonium salt) markedly attenuated the activatio n of p38 MAPK and JNK. Conversely, the selective protein kinase C inhi bitor calphostin C did not block D-1 dopamine receptor-stimulated acti vation of p38 MARK and JNK. These results demonstrate, for the first t ime, that the G(s)-coupled D-1 dopamine receptor activates the p38 MAR K and JNK signaling pathways by a protein kinase A-dependent mechanism .