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.
Nairn
Angus C
AC
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021, USA. angus.nairn@yale.edu
Svenningsson
Per
P
Nishi
Akinori
A
Fisone
Gilberto
G
Girault
Jean-Antoine
JA
Greengard
Paul
P
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D013287:Illicit Drugs / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D017072:Neostriatum / Q000166:cytology / Q000201:enzymology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009474:Neurons / Q000201:enzymology; D018377:Neurotransmitter Agents / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D019966:Substance-Related Disorders / Q000378:metabolism*
D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D013287:Illicit Drugs; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D010750:Phosphoproteins; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases