Amplification of dopaminergic signaling by a positive feedback loop

Dopamine and cAMP-regulated phosphoprotein of M-r 32,000 (DARPP-32) plays a n obligatory role in most of the actions of dopamine. in resting neostriata l slices, cyclin-dependent kinase 5 (Cdk5) phosphorylates DARPP-32 at Thr-7 5. thereby reducing the efficacy of dopaminergic signaling. We report here that dopamine, in slices, and acute cocaine, in whole animals, decreases th e state of phosphorylation of striatal DARPP-32 at Thr-75 and thereby remov es this inhibitory constraint. This effect of dopamine is achieved through dopamine D1 receptor-mediated activation of cAMP-dependent protein kinase ( PKA). The activated PKA, by decreasing the state of phosphorylation of DARP P-32-Thr-75, deinhibits itself. Dopamine D2 receptor stimulation has the op posite effect. The ability of activated PKA to reduce the state of phosphor ylation of DARPP-32-Thr-75 is apparently attributable to increased protein phosphatase-2A activity, with Cdk5 being unaffected. Together, these result s indicate that via positive feedback mechanisms, Cdk5 signaling and PKA si gnaling are mutually antagonistic.