Control of cyclin-dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability.
Although the roles of cyclin-dependent kinase 5 (Cdk5) in neurodevelopment and neurodegeneration have been studied extensively, regulation of Cdk5 activity has remained largely unexplored. We report here that glutamate, acting via NMDA or kainate receptors, can induce a transient Ca(2+)/calmodulin-dependent activation of Cdk5 that results in enhanced autophosphorylation and proteasome-dependent degradation of a Cdk5 activator p35, and thus ultimately down-regulation of Cdk5 activity. The relevance of this regulation to synaptic plasticity was examined in hippocampal slices using theta burst stimulation. p35(-/-) mice exhibited a lower threshold for induction of long-term potentiation. Thus excitatory glutamatergic neurotransmission regulates Cdk5 activity through p35 degradation, and this pathway may contribute to plasticity.
Wei
Fan-Yan
FY
Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Minami-osawa, Hachiohji, Tokyo, Japan.
Tomizawa
Kazuhito
K
Ohshima
Toshio
T
Asada
Akiko
A
Saito
Taro
T
Nguyen
Chan
C
Bibb
James A
JA
Ishiguro
Koichi
K
Kulkarni
Ashok B
AB
Pant
Harish C
HC
Mikoshiba
Katsuhiko
K
Matsui
Hideki
H
Hisanaga
Shin-Ichi
S
D000818:Animals; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000235:genetics / Q000378:metabolism*
C492236:Cdk5r1 protein, mouse; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases