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Molecular Pharmacology

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Research ArticleArticle

Increased Site-Specific Phosphorylation of Tyrosine Hydroxylase Accompanies Stimulation of Enzymatic Activity Induced by Cessation of Dopamine Neuronal Activity

Jow Y. Lew, Antonio Garcia-Espana, Kwan Y. Lee, Kenneth D. Carr, Menek Goldstein, John W. Haycock and Emanuel Meller
Molecular Pharmacology February 1999, 55 (2) 202-209; DOI: https://doi.org/10.1124/mol.55.2.202
Jow Y. Lew
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Antonio Garcia-Espana
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Kwan Y. Lee
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Kenneth D. Carr
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Menek Goldstein
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John W. Haycock
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Emanuel Meller
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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 γ-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 K mfor the cofactor tetrahydrobiopterin (3-fold). The effects of GBL and hemitransection were abolished or attenuated by pretreatment with the DA agonistR-(−)-N-n-propylnorapomorphine (NPA; 30 μg/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.

Footnotes

    • Received June 15, 1998.
    • Accepted November 6, 1998.
  • Send reprint requests to: Dr. Emanuel Meller, Department of Psychiatry, New York University Medical Center, 550 First Ave, New York, NY 10016. E-mail:emanuel.meller{at}ccmail.med.nyu.edu

  • ↵1 Deceased, October 18, 1997.

  • This work was supported by National Institute of Health Grants MH02717 (E.M.) and NS25134 (J.W.H.).

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (2)
Molecular Pharmacology
Vol. 55, Issue 2
1 Feb 1999
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Research ArticleArticle

Increased Site-Specific Phosphorylation of Tyrosine Hydroxylase Accompanies Stimulation of Enzymatic Activity Induced by Cessation of Dopamine Neuronal Activity

Jow Y. Lew, Antonio Garcia-Espana, Kwan Y. Lee, Kenneth D. Carr, Menek Goldstein, John W. Haycock and Emanuel Meller
Molecular Pharmacology February 1, 1999, 55 (2) 202-209; DOI: https://doi.org/10.1124/mol.55.2.202

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Research ArticleArticle

Increased Site-Specific Phosphorylation of Tyrosine Hydroxylase Accompanies Stimulation of Enzymatic Activity Induced by Cessation of Dopamine Neuronal Activity

Jow Y. Lew, Antonio Garcia-Espana, Kwan Y. Lee, Kenneth D. Carr, Menek Goldstein, John W. Haycock and Emanuel Meller
Molecular Pharmacology February 1, 1999, 55 (2) 202-209; DOI: https://doi.org/10.1124/mol.55.2.202
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