Beyond the Dopamine Receptor: the DARPP-32/Protein Phosphatase-1 Cascade

• Published in: Neuron Vol. 23; no. 3; pp. 435 - 447
• Main Authors: Greengard, Paul, Allen, Patrick B., Nairn, Angus C.
• Format: Book Review Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.1999
• Subjects: Animals; Brain - enzymology; Brain Chemistry - physiology; DARPP-32 protein; Dopamine and cAMP-Regulated Phosphoprotein 32; Enzyme Inhibitors - metabolism; Nerve Tissue Proteins - physiology; nigrostriatum; Phosphoprotein Phosphatases - physiology; Phosphoproteins; Protein Phosphatase 1; Receptors, Dopamine - physiology
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/S0896-6273(00)80798-9

Of the many slow-acting neurotransmitters utilized by the mammalian central nervous system, dopamine has received by far the most attention. There are major medical reasons for this interest in understanding the nature of dopaminergic neurotransmission. Parkinson's disease is attributable to a selective degeneration of midbrain nigrostriatal dopaminergic neurons. Huntington's chorea is caused by a deterioration of dopaminoceptive projection neurons in the neostriatum. Virtually all anti-schizophrenic drugs in current use act as antagonists at a major subclass of dopamine receptors, supporting the conjecture that aberrations in dopaminergic neurotransmission contribute to the symptomatology of schizophrenia. Attention deficit hyperactivity disorder (ADHD) symptoms are greatly alleviated by drugs that regulate dopaminergic transmission. Finally, drugs of abuse of the cocaine, amphetamine, and opiate classes, as well as nicotine and alcohol, achieve some of their addictive actions by modifying dopaminergic transmission. Despite the widespread interest in, and clinical importance of, dopaminergic signaling, little was known until recently concerning the molecular and cellular basis for the actions of dopamine on its target cells. In this article, we review recent studies that demonstrate that a phosphoprotein, known by the acronym DARPP-32 (dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein, 32 kDa), plays a central role in the biology of dopaminoceptive neurons. Dopamine and numerous other neurotransmitters that have been found in the neostriatum and shown to have physiological effects on dopaminoceptive neurons alter the phosphorylation and/or dephosphorylation of DARPP-32.