Identification of tyrosine hydroxylase as a physiological substrate for Cdk5

Janice W. Kansy, S. Colette Daubner, Akinori Nishi, Naoki Sotogaku, Michael D. Lloyd, Chan Nguyen, Lin Lu, John W. Haycock, Bruce T. Hope, Paul F. Fitzpatrick, James A. Bibb

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Cyclin-dependent kinase 5 (Cdk5) is emerging as a neuronal protein kinase involved in multiple aspects of neurotransmission in both post- and presynaptic compartments. Within the reward/motor circuitry of the basal ganglia, Cdk5 regulates dopamine neurotransmission via phosphorylation of the postsynaptic signal transduction pathway integrator, DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein, Mr 32 000). Cdk5 has also been implicated in regulating various steps in the presynaptic vesicle cycle. Here we report that Cdk5 phosphorylates tyrosine hydroxylase (TH), the key enzyme for synthesis of dopamine. Using phosphopeptide mapping, site-directed mutagenesis, and phosphorylation state-specific antibodies, the site was identified as Ser31, a previously defined extracellular signal-regulated kinases 1/2 (ERK1/2) site. The phosphorylation of Ser31 by Cdk5 versus ERK1/2 was investigated in intact mouse striatal tissue using a pharmacological approach. The results indicated that Cdk5 phosphorylates TH directly and also regulates ERK1/2-dependent phosphorylation of TH through the phosphorylation of mitogen-activated protein kinase kinase 1 (MEK1). Finally, phospho-Ser31 TH levels were increased in dopaminergic neurons of rats trained to chronically self-administer cocaine. These results demonstrate direct and indirect regulation of the phosphorylation state of a Cdk5/ERK1/2 site on TH and suggest a role for these pathways in the neuroadaptive changes associated with chronic cocaine exposure.

Original languageEnglish (US)
Pages (from-to)374-384
Number of pages11
JournalJournal of Neurochemistry
Volume91
Issue number2
DOIs
StatePublished - Oct 1 2004

Keywords

  • Cdk5
  • Cocaine
  • Dopamine
  • MARK
  • Phosphorylation
  • Tyrosine hydroxylase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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  • Cite this

    Kansy, J. W., Daubner, S. C., Nishi, A., Sotogaku, N., Lloyd, M. D., Nguyen, C., Lu, L., Haycock, J. W., Hope, B. T., Fitzpatrick, P. F., & Bibb, J. A. (2004). Identification of tyrosine hydroxylase as a physiological substrate for Cdk5. Journal of Neurochemistry, 91(2), 374-384. https://doi.org/10.1111/j.1471-4159.2004.02723.x