Regulation of Tyrosine Hydroxylase Activity and Phosphorylation at Ser 19 and Ser 40 via Activation of Glutamate NMDA Receptors in Rat Striatum

• Published in: Journal of neurochemistry Vol. 74; no. 6; pp. 2470 - 2477
• Main Authors: Lindgren, Niklas, Xu, Zhi‐Qing David, Lindskog, Maria, Herrera‐Marschitz, Mario, Goiny, Michel, Haycock, John, Goldstein, Menek, Hökfelt, Tomas, Fisone, Gilberto
• Format: Journal Article
• Language: English
• Published: 06-06-2000
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2000.0742470.x

The activity of tyrosine hydroxylase, the rate‐limiting enzyme in the biosynthesis of dopamine, is stimulated by phosphorylation. In this study, we examined the effects of activation of NMDA receptors on the state of phosphorylation and activity of tyrosine hydroxylase in rat striatal slices. NMDA produced a time‐and concentration‐dependent increase in the levels of phospho‐Ser
19
‐tyrosine hydroxylase in nigrostriatal nerve terminals. This increase was not associated with any changes in the basal activity of tyrosine hydroxylase, measured as DOPA accumulation. Forskolin, an activator of adenylyl 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. In addition, NMDA reduced the increase in phospho‐Ser
40
‐tyrosine hydroxylase produced by okadaic acid, an inhibitor of protein phosphatase 1 and 2A, but not by a cyclic AMP analogue, 8‐bromo‐cyclic AMP. These results indicate that, in the striatum, glutamate decreases tyrosine hydroxylase phosphorylation at Ser
40
via activation of NMDA receptors by reducing cyclic AMP production. They also provide a mechanism for the demonstrated ability of NMDA to decrease tyrosine hydroxylase activity and dopamine synthesis.