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

striatum, and therefore function to integrate all input to Introduction this brain region. DARPP-32 is expressed in very high Of the many slow-acting neurotransmitters utilized by concentration (z50 mM) in virtually all medium spiny the mammalian central nervous system, dopamine has neurons (Ouimet et al., 1984, 1998) (Figure 2). Medium received by far the most attention. There are major medispiny neurons contain both D1 class (D1, D5) and D2 class cal reasons for this interest in understanding the nature (D2, D3, D4) dopamine receptors (Sibley and Monsma, of dopaminergic neurotransmission. Parkinson’s dis1992). Analysis of dopamine action is complicated by ease is attributable to a selective degeneration of midthe differential distribution of these receptors. While still brain nigrostriatal dopaminergic neurons. Huntington’s controversial, the prevailing view is that D1 and D2 dopachorea is caused by a deterioration of dopaminoceptive mine receptors are largely segregated in two subpopulaprojection neurons in the neostriatum. Virtually all antitions of medium spiny neurons (Gerfen et al., 1990; schizophrenic drugs in current use act as antagonists Hersch et al., 1995; Yung et al., 1995). The D1 class are at a major subclass of dopamine receptors, supporting expressed predominantly in striatonigral neurons (direct the conjecture that aberrations in dopaminergic neuropathway) and are colocalized with the neuropeptides transmission contribute to the symptomatology of schizodynorphin and substance P. In contrast, the D2 class phrenia. Attention deficit hyperactivity disorder (ADHD) of receptors are found predominantly in striatopallidal symptoms are greatly alleviated by drugs that regulate neurons (indirect pathway) and are colocalized with endopaminergic transmission. Finally, drugs of abuse of kephalin. However, based on physiological analysis of the cocaine, amphetamine, and opiate classes, as well the actions of D1 and D2 agonists (see below), and as nicotine and alcohol, achieve some of their addictive analysis of mRNA expression, it appears likely that a actions by modifying dopaminergic transmission. significant subpopulation of medium spiny neurons exDespite the widespread interest in, and clinical imporpress both D1 and D2 classes of receptors (Surmeier tance of, dopaminergic signaling, little was known until et al., 1996). recently concerning the molecular and cellular basis for Medium spiny neurons contain both NMDA and nonthe actions of dopamine on its target cells. In this article, NMDA classes of glutamate receptors and receive major we review recent studies that demonstrate that a phosexcitatory inputs from glutamate-containing corticostriphoprotein, known by the acronym DARPP-32 (dopaatal nerve terminals (reviewed by Gerfen, 1992; Smith mine and cyclic adenosine 39,59-monophosphate-reguet al., 1998). In addition to glutamate and dopamine, lated phosphoprotein, 32 kDa), plays a central role in medium spiny neurons receive an inhibitory input from the biology of dopaminoceptive neurons. Dopamine and GABA-containing nerve terminals via recurrent collaternumerous other neurotransmitters that have been found als (Gerfen, 1992; Smith et al., 1998). Adenosine A2A in the neostriatum and shown to have physiological efreceptors are expressed specifically on striatopallidal fects on dopaminoceptive neurons alter the phosphoryneurons (Svenningsson et al., 1997), where they are lation and/or dephosphorylation of DARPP-32 (Figure coexpressed with D2 receptors. Opiate receptors (Man1). In its phosphorylated but not dephosphorylated form, sour et al., 1987), as well as receptors for neuropeptides DARPP-32 is an extremely potent inhibitor of protein such as cholecystokinin (CCK) and neurotensin (Fuxe phosphatase-1 (PP-1), a major multifunctional serine/ et al., 1995; Ferraro et al., 1998), are also found in the threonine protein phosphatase in the brain. PP-1, in turn, striatum and have been shown to influence the activity regulates the phosphorylation state and activity of many of medium spiny neurons. The striatum also contains a downstream physiological effectors, including various small population of interneurons, including large aspiny neurotransmitter receptors and voltage-gated ion channeurons that release acetylcholine, and several types of nels. Studies of mice lacking the DARPP-32 gene have medium aspiny neurons that contain somatostatin and provided convincing evidence that this protein plays an neuropeptide Y (Figueredo-Cardenas et al., 1996). essential role in mediating the actions and interactions