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. 2000 Oct 24;97(23):12840–12845. doi: 10.1073/pnas.220410397

Figure 6.

Figure 6

Model illustrating the regulation of dopamine signaling by Cdk5/phospho-Thr-75 DARPP-32 and regulation of the Cdk5/phospho-Thr-75 DARPP-32 pathway by dopamine. The Cdk5 signaling and PKA signaling pathways, through a positive feedback loop, are mutually antagonistic. (Left) Under basal conditions, phosphorylation of DARPP-32 at Thr-75 by Cdk5 causes, successively, inhibition of PKA, inactivation of PP-2A, and decreased dephosphorylation of phospho-Thr-75 DARPP-32. Inhibition of PKA also results in decreased phosphorylation of DARPP-32-Thr-34 and, therefore, in activation of PP-1. Inhibition of PKA and activation of PP-1 synergistically reduce the phosphorylation of various substrates. (Right) Dopamine, by sequentially activating dopamine D1 receptors, PKA and PP-2A, reduces the level of phospho-Thr-75 DARPP-32. Dephosphorylation of DARPP-32 at Thr-75 by PP-2A removes the inhibition of PKA. Activation of PKA also results in increased phosphorylation of DARPP-32-Thr-34 and in inhibition of PP-1. Activation of PKA and inhibition of PP-1 synergistically increase the phosphorylation of various substrates.