Regulation of Cdk5 activity and function in neurons

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Cdk5, a cdc2-related protein kinase expressed in postmitotic neurons, is activated by association with brain specific activator p35 or p39. By support from the Grant-in-Aid for Scientific Research, we have analyzed the activation mechanism of Cdk5 in neurons of mouse or rat brains. p35 is a short life protein degraded by proteasome. It was unknown how degradation of p35 is triggered in neurons. We found that p35 was degraded when neurons were treated with glutamate, an excitatory neurotransmitter. Degradation occurred in postsynaptic regions where glutamate receptors are rich. Inactivation of Cdk5 activity accompanied by degradation of p35 stimulated the activation of Ca-calmodulin kinase II, which is involved in induction of long term potentiation, a basic mechanism of memory formation. p35 was shown to associate with membranes through its myristoylation at the second Gly. Further, association of p35 with membranes suppressed the kinase activity of Cdk5. Membrane bound CdkS/p35 was activated when they were released from membranes by treatment with nonionic detergent. p35 is cleaved to p25 by calpain, a Ca-activated cysteine protease, resulting in induction of neuronal cell death. The cleavage was induced when neurons were suffered with endoplasmic reticulum-stress by Thapsigardin. Thapsigardin tretment induced neuronal cell death 2 -4 days after treatment and the cell death was suppressed by Cdk5 inhibitor Roscovitine. p25 generated was translocated into nucleus and increased the kinase activity of Cdk5 in the nucleus. We think that Cdk5//p25 induce neuronal cell death by activating cell cycle machinery in post-mitotic neurons.