Zhen X, Uryu K, Wang H Y, Friedman E
Laboratory of Molecular Pharmacology, Department of Pharmacology, MCP-Hahnemann School of Medicine, Allegheny University of the Health Sciences, Philadelphia, Pennsylvania 19129, USA.
Mol Pharmacol. 1998 Sep;54(3):453-8. doi: 10.1124/mol.54.3.453.
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 microM SKF38393. In contrast, 10 microM quinpirole, a D2 dopamine receptor agonist, did not activate p38 MAPK or JNK. Treatment of cells with 10 muM SCH23390, 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 microM H-89 or 10 microM 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 Gs-coupled D1 dopamine receptor activates the p38 MAPK and JNK signaling pathways by a protein kinase A-dependent mechanism.
我们研究了多巴胺D1受体激动对人神经母细胞瘤SK-N-MC细胞中丝裂原活化蛋白激酶（MAPK）激活的影响。我们发现，D1多巴胺受体激动剂SKF38393诱导p38 MAPK和c-Jun氨基末端激酶（JNK）出现类似的时间和剂量相关的激活，而细胞外信号调节激酶活性不受D1多巴胺受体激动的影响。在用100 microM SKF38393孵育15分钟后，观察到p38 MAPK和JNK的最大激活。相比之下，D2多巴胺受体激动剂10 microM喹吡罗未激活p38 MAPK或JNK。用10 muM SCH23390（一种D1多巴胺受体拮抗剂）处理细胞，可显著抑制SKF38393对这两种激酶的激活。这些结果表明，p38 MAPK和JNK信号通路的激活是由SK-N-MC神经母细胞瘤细胞中的多巴胺D1受体介导的。此外，二丁酰环磷腺苷模仿了SKF38393介导的对p38 MAPK和JNK的刺激。用1 microM H-89或10 microM 3',5'-环磷硫代腺苷（Rp-异构体，三乙铵盐）抑制蛋白激酶A可显著减弱p38 MAPK和JNK的激活。相反，选择性蛋白激酶C抑制剂钙泊三醇C并未阻断D1多巴胺受体刺激的p38 MAPK和JNK的激活。这些结果首次证明，Gs偶联的D1多巴胺受体通过蛋白激酶A依赖性机制激活p38 MAPK和JNK信号通路。
