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

Bogachan Sahin1, Ammar H Hawasli, Robert W Greene

  • 1Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9070, United States.

European Journal of Pharmacology
|January 15, 2008
PubMed

Insights

Protein kinase C (PKC) indirectly regulates Cyclin-dependent kinase 5 (Cdk5) activity in the brain by affecting Cdk5 substrates, not Cdk5 itself. This suggests PKC influences Cdk5 through other binding partners.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • Cyclin-dependent kinase 5 (Cdk5) is crucial for brain development and function, involved in synaptic plasticity and neurodegenerative diseases.
  • The precise in vivo regulatory mechanisms of Cdk5 activity remain largely uncharacterized.

Purpose of the Study:

  • To investigate whether protein kinase C (PKC) modulates Cdk5 activity within the central nervous system.
  • To elucidate the molecular interactions between PKC and Cdk5 signaling pathways.

Main Methods:

  • Assessed phosphorylation levels of Cdk5 substrates (inhibitor-1 and DARPP-32) in response to PKC activation and inhibition in striatal slices.
  • Examined Cdk5 and cofactor (p35, p25) levels and Cdk5 activity in PKC-altered conditions.
  • Utilized PKC activators (phorbol ester) and inhibitors (Ro-32-0432), as well as gene-deficient mice (PKC-alpha knockout).

Main Results:

  • PKC activation decreased phosphorylation of Cdk5 substrates (inhibitor-1, DARPP-32) in a dose- and time-dependent manner.
  • PKC inhibition reversed these effects; PKC-alpha deficiency increased substrate phosphorylation.
  • PKC did not directly phosphorylate Cdk5 or its cofactors (p25, p35), and Cdk5 activity remained unchanged.

Conclusions:

  • PKC regulates Cdk5 substrate phosphorylation indirectly, likely by interacting with Cdk5 regulatory partners other than its primary neuronal cofactors.
  • This indirect mechanism highlights a novel regulatory pathway influencing Cdk5 function in the brain.

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