D2 dopamine receptors induce mitogen-activated protein kinase and cAMP response element-binding protein phosphorylation in neurons

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The National Academy of Sciences

RESUMO

Dopamine, by activating D1- and D2-class receptors, plays a significant role in regulating gene expression. Although much is known about D1 receptor-regulated gene expression, there has been far less information on gene regulation mediated by D2 receptors. In this study, we show that D2 receptors can activate the mitogen-activated protein kinase (MAPK) and the cAMP response element-binding protein (CREB) in neurons. Treatment of brain slices with the D2 receptor agonist quinpirole induced rapid phosphorylation of MAPK and CREB. The neuroleptic drug eticlopride, a highly selective D2 receptor antagonist, blocked the quinpirole-induced phosphorylation of MAPK and CREB. D2 receptor-induced MAPK phosphorylation depended on intracellular Ca2+ elevation, protein kinase C activation, and MAPK kinase activation, but not on the protein tyrosine kinase Pyk2, even though quinpirole stimulated Pyk2 phosphorylation. D2 receptor-induced CREB phosphorylation was mediated by activation of protein kinase C and Ca2+/calmodulin-dependent protein kinase, but not MAPK. The dopamine and cAMP-regulated phosphoprotein DARPP-32 also was required for the regulation of MAPK and CREB phosphorylation by D2 receptors. Our results suggest that MAPK and CREB signaling cascades are involved in the regulation of gene expression and other long-term effects of D2 receptor activation.

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