The role of DARPP-32 in the actions of drugs of abuse.

The dopamine- and cAMP-regulated phosphoprotein, M(r) 32 kDa (DARPP-32), plays a key role in dopaminoceptive neurons in the neostriatum (and likely in other brain regions) in signal transduction pathways regulated by a variety of neurotransmitters, neuromodulators, and neuropeptides. Phosphorylation at Thr34 by protein kinase A converts DARPP-32 into a potent inhibitor of the multifunctional serine/threonine protein phosphatase, PP-1. Phosphorylation at Thr75 by Cdk5 converts DARPP-32 into an inhibitor of protein kinase A. The state of phosphorylation of DARPP-32 at Thr34 also depends on the phosphorylation state of Ser102 and Ser137, which are phosphorylated by CK2 and CK1, respectively. By virtue of its regulation of its four phosphorylation sites by a large number of physiological and pharmacological stimuli, and through its ability to modulate the activity of PP-1 and protein kinase A, DARPP-32 plays a key role in integrating a variety of electrophysiological, transcriptional, and behavioral responses. This review focuses on the critical role that DARPP-32 plays in mediating the actions of a broad range of drugs of abuse.