Dopamine D-2 receptors regulate tyrosine hydroxylase activity and phosphorylation at Ser40 in rat striatum

In the striatum, dopamine release is inhibited by activation of dopamine D- 2 autoreceptors. Changes in dopamine release have been attributed to change s in the synthesis of dopamine, which is regulated via phosphorylation of t yrosine hydroxlase (TH), the rate-limiting enzyme in the synthesis of catec holamines. Here, we have studied the involvement of dopamine D-2 receptors in the regulation of TH phosphorylation at distinct seryl residues, using p hosphorylation site-specific antibodies and a preparation of rat striatal s lices. The D-2 receptor agonist, quinpirole, reduced basal TH phosphorylati on at Ser40 but not at Ser19 or Ser31. Quinpirole was also able to reduce t he increase in Ser40 phosphorylation caused by forskolin, an activator of a denylyl cyclase, without affecting the increase in Ser19 phosphorylation pr oduced by the glutamate receptor agonist, N-methyl-d-aspartate (NMDA). In a ddition, the dopamine D-2 receptor agonist reduced both basal and forskolin -stimulated activity of TH, measured as 3,4-dihydroxyphenylalanine (DOPA) a ccumulation. Quinpirole decreased phosphorylation of Ser40 induced by okada ic acid, an inhibitor of protein phoshatase 1 and 2A and Ro-20-1724, a phos phodiesterase inhibitor. In contrast, quinpirole did not affect the increas e in Ser40 phosphorylation caused by the cAMP analogue, 8-Br-cAMP. These da ta indicate that, in the striatum, activation of dopamine D-2 receptors res ults in selective inhibition of TH phosphorylation at Ser40 via reduction o f the activity of adenylyl cyclase. They also provide a molecular mechanism accounting for the ability of dopamine D-2 autoreceptors to inhibit dopami ne synthesis and release from nigrostriatal nerve terminals.