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- Title
Regulation of Tyrosine Hydroxylase Activity and Phosphorylation at Ser<sup>19</sup> and Ser<sup>40</sup> via Activation of Glutamate NMDA Receptors in Rat Striatum.
- Authors
Lindgren, Niklas; Xu, Zhi-Qing David; Lindskog, Maria; Herrera-Marschitz, Mario; Goiny, Michel; Haycock, John; Goldstein, Menek; Hökfelt, Tomas; Fisone, Gilberto
- Abstract
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-Ser19-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 Ser40 and caused a significant increase in DOPA accumulation. NMDA reduced forskolin-mediated increases in both Ser40 phosphorylation and DOPA accumulation. In addition, NMDA reduced the increase in phospho-Ser40-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 Ser40 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.
- Publication
Journal of Neurochemistry, 2000, Vol 74, Issue 6, p2470
- ISSN
0022-3042
- Publication type
Academic Journal
- DOI
10.1046/j.1471-4159.2000.0742470.x