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Enhanced activation of Ca 2+ /Calmodulin‐dependent protein kinase II upon downregulation of cyclin‐dependent kinase 5‐p35
Author(s) -
Hosokawa Tomohisa,
Saito Taro,
Asada Akiko,
Ohshima Toshio,
Itakura Makoto,
Takahashi Masami,
Fukunaga Kohji,
Hisanaga Shinichi
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20975
Subject(s) - cyclin dependent kinase 5 , downregulation and upregulation , postsynaptic potential , long term potentiation , autophosphorylation , microbiology and biotechnology , nmda receptor , chemistry , kinase , protein kinase a , postsynaptic density , stimulation , biology , cyclin dependent kinase 2 , neuroscience , biochemistry , receptor , gene
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 Ca 2+ /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 invitro 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 withNMDA facilitates CaMKII activation, leading to the easier induction of long‐term potentiation. © 2006 Wiley‐Liss, Inc.