Negative regulation of cyclin-dependent kinase 5 targets by protein kinase C

Bogachan Sahin, Ammar H. Hawasli, Robert W. Greene, Jeffery D. Molkentin, James A. Bibb

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed protein serine/threonine kinase essential for brain development and implicated in synaptic plasticity, dopaminergic neurotransmission, drug addiction, and neurodegenerative disorders. Relatively little is known about the molecular mechanisms that regulate the activity of Cdk5 in vivo. In order to determine whether protein kinase C (PKC) regulates Cdk5 activity in the central nervous system, the phosphorylation levels of two Cdk5 substrates were evaluated under conditions of altered PKC activity in vivo. Treatment of acute striatal slices with a PKC-activating phorbol ester caused a time- and dose-dependent decrease in the levels of phospho-Ser6 inhibitor-1, phospho-Ser67 inhibitor-1, and phospho-Thr75 dopamine- and cAMP-regulated phosphoprotein, Mr 32,000 (DARPP-32). This effect was reversed by the PKC inhibitor, Ro-32-0432. Moreover, phospho-Ser6 inhibitor-1, phospho-Ser67 inhibitor-1, and phospho-Thr75 DARPP-32 levels were elevated in brain tissue from mice lacking the gene for PKC-α. PKC did not phosphorylate Cdk5 or its cofactor, p25, in vitro. Striatal levels of the Cdk5 cofactor, p35, did not change in response to phorbol ester treatment. Furthermore, Cdk5 immunoprecipitated from striatal slices treated with phorbol ester had unaltered activity toward a control substrate in vitro. These results suggest that PKC exerts its effects on the phosphorylation state of Cdk5 substrates through an indirect mechanism that may involve the regulatory binding partners of Cdk5 other than its neuronal cofactors.

Original languageEnglish
Pages (from-to)270-275
Number of pages6
JournalEuropean Journal of Pharmacology
Volume581
Issue number3
DOIs
StatePublished - Mar 10 2008
Externally publishedYes

Keywords

  • Cdk5
  • DARPP-32
  • Inhibitor-1
  • PKC
  • Phorbol ester

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