Control of cyclin‐dependent kinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability

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Abstract
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 Ca2+/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.