Fig. 8.

Cyclic AMP mediates CREB phosohorylation by two different mechanism. a The distribution of activated PKA after stimulation with low levels of forskolin or dopamine, and after high levels of forskolin. b Low levels of forskolin increase local PKA activity which causes phosphorylation of the NMDAR1 receptor. Kinases activated intraneuronally by the NMDA receptor pathway phosphorylate CREB. NMDA receptors also stimulate PP1 activity through the DARPP-32 pathway, but the equilibrium favors kinase activity, as demonstrated by increased ¹³³Ser-CREB phosphorylation. Therefore, inhibition of NMDA receptors prevents CREB phosphorylation. The bold arrow points out the predominant action of the NMDA receptor pathway in the presence of low concentrations of forskolin. c High levels of forskolin stimulate sufficient amounts of PKA to directly phosphorylate ¹³³Ser-CREB. Kinases activated by NMDA receptors cannot further contribute to CREB phosphorylation, while the activation of calcineurin and the opposition to DARPP-32 phosphorylation attenuates CREB phosphorylation. The net effect of the NMDA receptor pathway is a decrease of high forskolin-stimulated ¹³³Ser-phospho-CREB levels. Therefore, inhibition of NMDA receptors increases CREB phosphorylation. The bold arrow points out the predominant action of the NMDA receptor pathway in the presence of high concentrations of forskolin.