Cdk5 and PKA produce opposing actions on DARPP-32, an important modulator of dopaminergic signaling. As discussed earlier, PKA phosphorylates DARPP-32 on Thr-34, which renders DARPP-32 active as an inhibitor of PP-1.71 Dopaminergic signaling increases PKA-mediated phosphorylation of DARPP-32 on Thr-34 and inhibits dephosphorylation by PP-1, amplifying dopamine-mediated PKA phosphorylation of downstream targets.72 Cdk5 negatively regulates dopaminergic signaling by phosphorylating DARPP-32 on Thr-75. This renders DARPP-32 an inhibitor of PKA and reduces PKA phosphorylation of DARPP-32 at Thr-34.73 Inhibition of Cdk5 with roscovitine decreases DARPP-32 phosphorylation of Thr-75, increases PKA-mediated whole-cell calcium currents,73 and potentiates cocaine-stimulated dopamine accumulation in mouse striatal slices.137 Cdk5 also can inhibit the ERK pathway through phosphorylation and inhibition of MEK. It may thus function in a negative feedback loop that prevents excessive ERK activity.138
