Regulation of tyrosine hydroxylase activity and phosphorylation at Ser(19)and Ser(40) via activation of glutamate NMDA receptors in rat striatum

The activity of tyrosine hydroxylase, the rate-limitingenzyme in the biosyn thesis of dopamine, is stimulated by phosphorylation. In this study, we exa mined the effects of activation of NMDA receptors on the state of phosphory lation and activity of tyrosine hydroxylase in rat striatal slices. NMDA pr oduced a time-and concentration-dependent increase in the levels of phospho -Ser(19)-tyrosine hydroxylase in nigrostriatal nerve terminals. This increa se was not associated with any changes in the basal activity of tyrosine hy droxylase, measured as DOPA accumulation. Forskolin, an activator of adenyl yl cyclase, stimulated tyrosine hydroxylase phosphorylation at Ser(40) and caused a significant increase in DOPA accumulation. NMDA reduced forskolin- mediated increases in both Ser(40) phosphorylation and DOPA accumulation. I n addition, NMDA reduced the increase in phospho-Se-40-tyrosine hydroxylase produced by okadaic acid, an inhibitor of protein phosphatase 1 and 2A, bu t not by a cyclic AMP analogue, 8-bromo-cyclic AMP. These results indicate that, in the striatum, glutamate decreases tyrosine hydroxylase phosphoryla tion at Ser(40) via activation of NMDA receptors by reducing cyclic AMP pro duction. They also provide a mechanism for the demonstrated ability of NMDA to decrease tyrosine hydroxylase activity and dopamine synthesis.