Dopaminergic signaling in midbrain neurons is essential to multiple brain functions and involves the activation of dopamine receptors,
such as D1 and D2, which regulate the phosphorylation state of DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein of Mr = 32,000). D1 receptor ligation causes activation of PKA and phosphorylation of DARPP-32 at Thr-34, which converts DARPP-32 to a potent inhibitor of protein phosphatase 1 (PP1). In addition, DARPP-32 is converted to an inhibitor of PKA via phosphorylation at Thr-75 by cyclin-dependent kinase 5 (Cdk5). D2 receptor ligation inhibits PKA and activates protein phosphatase 2B/calcineurin causing dephosphorylation of DARPP-32. The major function of DARPP-32 may be to inhibit the activity of PP1, which controls the phosphorylation state of neurotransmitter receptors, ion channels, ion pumps, and transcription factors. DARPP-32 -/- mice are defective in the physiologicial and behavioral responses to dopamine. Thus, DARPP-32, a bifunctional signal transduction molecule that differentially controls a Ser/Thr kinase and a Ser/Thr phosphatase, is a critical element of dopaminergic neurotransmission and normal brain function.