Enhanced activation of Ca2+/calmodulin-dependent protein kinase II upon downregulation of cyclin-dependent kinase 5-p35

Tomohisa Hosokawa, Taro Saito, Akiko Asada, Toshio Ohshima, Makoto Itakura, Masami Takahashi, Kohji Fukunaga, Shin Ichi Hisanaga

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Cyclin-dependent kinase 5 (Cdk5)-p35 is downregulated in cultured neurons by N-methyl-D-aspartate (NMDA) via the proteasomal degradation of p35. However, it is not known where in neurons this downregulation occurs or the physiologic meaning of the reaction. We show the enrichment of Cdk5 and p35 in the postsynaptic density and the NMDA-induced degradation of postsynaptic p35 using brain slices and cultured neurons. To evaluate the role of this downregulation, we examined the relationship between Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation and Cdk5 downregulation, as events downstream from NMDA stimulation. Glutamate or NMDA stimulation induced CaMKII autophosphorylation over a time course that mirrored the time course of p35 degradation. To simulate the downregulation of postsynaptic Cdk5 in in vitro experiments, we used the Cdk5 inhibitor roscovitine. The inhibition of Cdk5 activity by roscovitine enhanced CaMKII autophosphorylation and activation in cultured neurons, and in an isolated postsynaptic-density-enriched fraction. These results suggest that Cdk5 activity suppresses CaMKII activation, and that the downregulation of Cdk5 activity after treatment with NMDA facilitates CaMKII activation, leading to the easier induction of long-term potentiation.

Original languageEnglish
Pages (from-to)747-754
Number of pages8
JournalJournal of Neuroscience Research
Volume84
Issue number4
DOIs
Publication statusPublished - 2006 Sep 1
Externally publishedYes

Keywords

  • Ca/calmodulin-dependent protein kinase II
  • Cyclin-dependent kinase 5
  • Glutamate
  • Long-term potentiation
  • N-methyl-D-aspartate
  • p35

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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