Article

Increased site-specific phosphorylation of tyrosine hydroxylase accompanies stimulation of enzymatic activity induced by cessation of dopamine neuronal activity

Department of Biochemistry and Molecular Biology , Louisiana State University Health Sciences Center New Orleans, New Orleans, Louisiana, United States
Molecular Pharmacology (Impact Factor: 4.13). 03/1999; 55(2):202-9.
Source: PubMed

ABSTRACT

Activation of striatal dopamine (DA) neurons by neuroleptic treatment or by electrical stimulation of the nigrostriatal pathway increases the activity of tyrosine hydroxylase (TH). The increase is mediated by phosphorylation of the enzyme. However, abolition of DA neuronal activity [by gamma-butyrolactone (GBL) treatment or transection of the nigrostriatal pathway] also increases TH activity. Quantitative blot immunolabeling experiments using site- and phosphorylation state-specific antibodies to TH demonstrated that GBL treatment (750 mg/kg, 35 min) significantly increased phosphorylation at Ser19 (+40%) and Ser40 (+217%) without altering Ser31 phosphorylation. Concomitantly, GBL treatment [along with the 3,4-dihydroxyphenylalanine (dopa) decarboxylase inhibitor NSD-1015, 100 mg/kg, 30 min] increased in vivo striatal dopa accumulation and in vitro TH activity 3-fold. Likewise, cerebral hemitransection of the nigrostriatal pathway significantly increased phosphorylation of TH at Ser19 (+89%) and Ser40 (+158%) but not at Ser31; dopa levels were increased accordingly (+191%). Kinetic analysis of TH activity established that GBL treatment and hemitransection primarily decreased the Km for the cofactor tetrahydrobiopterin (3-fold). The effects of GBL and hemitransection were abolished or attenuated by pretreatment with the DA agonist R-(-)-N-n-propylnorapomorphine (NPA; 30 microgram/kg, 40 min), presumably via stimulation of inhibitory presynaptic DA autoreceptors. NPA dose-response curves for reversal of GBL-induced dopa accumulation and Ser40 phosphorylation were identical; however, only the highest dose of NPA reversed the small and variable increase in Ser19 phosphorylation. Thus, TH activity seems to be regulated by phosphorylation in both hyper- and hypoactive striatal DA neurons; in the latter case, activation seems to be caused by selective phosphorylation of Ser40.

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    • "To test this, we presented females claiming nest boxes with an unfamiliar female as a competitor, and assessed the presence of phosphorylated tyrosine hydroxylase (pTH) via immunohistochemistry. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of dopamine, and phosphorylation of TH occurs during short-term regulation of this enzyme and triggers synthesis of catecholamines (Dunkley et al., 2004; Kumer and Vrana, 1996; Lew et al., 1999). It is generally accepted that such up-regulation of DA synthesis occurs after the release of either DA or NE (Dunkley et al., 2004; Gordon et al., 2008; Wakade et al., 1988). "
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    • "To test this, we presented females claiming nest boxes with an unfamiliar female as a competitor, and assessed the presence of phosphorylated tyrosine hydroxylase (pTH) via immunohistochemistry. Tyrosine hydroxylase (TH) is the rate-limiting enzyme in the synthesis of dopamine, and phosphorylation of TH occurs during short-term regulation of this enzyme and triggers synthesis of catecholamines (Dunkley et al., 2004; Kumer and Vrana, 1996; Lew et al., 1999). It is generally accepted that such up-regulation of DA synthesis occurs after the release of either DA or NE (Dunkley et al., 2004; Gordon et al., 2008; Wakade et al., 1988). "
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    • "Locomotor activity and rota-rod performance were measured as described previously [13]. Striatal dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanilic acid (HVA), and TH activity were measured by HPLC-electrochemical detection [13, 14]. Dopamine turnover rate was calculated by the ratio of [(DOPAC + HVA)/ dopamine]. "
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