Map of dopamine signaling in the neostriatum under normal and pathophysiological conditions

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Dopamine plays a central role in the regulation of psychomotor function in the brain. Many of the actions of dopamine are mediated through DARPP-32 (dopamine-and cAMP-regulated phosphoprotein of M_r 32 kDa). When DARPP-32 is phosphorylated on Thr34, it is converted into a potent inhibitor of protein phosphatase-1 (PP-1), and thereby controls the phosphorylation state and activity of many downstream physiological effectors. It is extremely important to identify signaling cascades activated by dopamine and other neurotransmitters under normal and pathophysiological conditions.In analysis of dopamine/DARPP-32 signaling under normal conditions, the phosphorylation site of DARPP-32 at Ser97 by CK2 was found to function as nuclear export signal. DARPP-32 at Ser97 is highly phosphorylated by CK2. The phosphorylated form of DARPP-32 enters into and is exported from nucleus. Phospho-Ser97 DARPP-32 is dephosphorylated by the dopamine D1 receptor/PKA/PP2A signaling cascade, and the dephospho-Ser97 DARPP-32 is not exported from nucleus and accumulates in nucleus. Since the dopamine D1 receptor/PKA/PP2A signaling cascade leads to phosphorylate DARPP-32 at Thr34, phospho-Thr34 DARPP-32 inhibits PP-1 and regulates the transcription of genes. In analysis of Mecp^<208/Y> mutant mice (a model mouse of Rett syndrome), we found that dopamine D1 receptor signaling is enhanced in neostriatal neurons after 20 weeks of age. In the study of methamphetamine sensitization, we found that the proportions of dopamine D1^<High> and D2^<High> receptors were increased in the striatum from MAP-sensitized rats, and that repeated administration of R-(+)-SKF38393 reversed the increased proportions of dopamine Dl^<High> and D2^<High> receptors in MAP-sensitized rats.