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

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.