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 Citations (Scopus)

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

Fingerprint

Cyclin-Dependent Kinase 5
Protein Kinase C
Corpus Striatum
Dopamine and cAMP-Regulated Phosphoprotein 32
Phorbol Esters
Phosphorylation
Dopamine Agents
Neuronal Plasticity
Protein C Inhibitor
Protein-Serine-Threonine Kinases
Brain
Protein Kinase Inhibitors
Proline
Synaptic Transmission
Neurodegenerative Diseases
Substance-Related Disorders
Central Nervous System

Keywords

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

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Negative regulation of cyclin-dependent kinase 5 targets by protein kinase C. / Sahin, Bogachan; Hawasli, Ammar H.; Greene, Robert W.; Molkentin, Jeffery D.; Bibb, James A.

In: European Journal of Pharmacology, Vol. 581, No. 3, 10.03.2008, p. 270-275.

Research output: Contribution to journalArticle

Sahin, Bogachan ; Hawasli, Ammar H. ; Greene, Robert W. ; Molkentin, Jeffery D. ; Bibb, James A. / Negative regulation of cyclin-dependent kinase 5 targets by protein kinase C. In: European Journal of Pharmacology. 2008 ; Vol. 581, No. 3. pp. 270-275.
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