Figure 5.

Model of signaling cascades involved in D₂ receptor-induced phosphorylation of MAPK and CREB. In this model, D₂ receptors couple to the Gq protein and activate PLCβ, which promotes the hydrolysis of phosphatidlyinositide biphosphate (PIP₂) to form 1,2-diacylglycerol and 1,4,5-inositol trisphosphate. 1,2-diacylglycerol activates PKC, and 1,4,5-inositol trisphosphate causes the release of Ca²⁺ from intracellular stores. PKC and Ca²⁺ together activate Ras/Raf/MEK/MAPK signaling through mechanisms independent of Pyk2. CaMK activated by elevation of intracellular Ca²⁺, together with activated PKC, phosphorylate CREB. DARPP-32 is involved in the D₂ receptor regulation of phosphorylation of both MAPK and CREB. The mechanism by which this occurs most likely involves regulation by D₂ receptors of the phosphorylation state of DARPP-32, and therefore of the activity of protein phosphatase 1 (29), which dephosphorylates CREB.