The novel function of cyclin-dependent kinase 5, a role in long term potentiation

Cdk5是一种在有丝分裂后神经元中表达的cdc2相关激酶，通过与脑特异性激活剂p35结合而被激活。已经表明蛋白酶钙蛋白酶将p35转化为p25参与神经元细胞死亡。另一方面，p35蛋白在活的神经元中通过蛋白酶体降解而迅速翻转。在这项研究中，我们发现，p35的磷酸化参与其蛋白水解降解的控制，并且p35的磷酸化状态以发育的方式变化。p35的磷酸化形式对钙蛋白酶的切割具有抗性，并且对蛋白酶体降解更敏感。p35的非磷酸化形式对蛋白酶体降解更具抗性，但对钙蛋白酶依赖性切割产生p25更敏感。Cdk5对p35的自磷酸化抑制了钙蛋白酶对p25的切割，而自磷酸化促进了p35的蛋白酶体降解。磷酸化形式的p35在胎儿脑中更普遍，而未磷酸化形式的p35发生在成人脑中。这些结果表明，p35的自磷酸化作为一种保护机制，抑制p25在发育中的大脑的产生。

Cdk5, a cdc2-related kinase expressed in postmitotic neurons, is activated by association with a brain-specific activator, p35. It has been suggested the conversion of p35 to p25 by the protease calpain is involved in neuronal cell death. On the other hand, p35 protein is rapidly turned over via proteasomal degradation in living neurons. In this study, we found that the phosphorylation of p35 is involved in the control of its proteolytic degradation, and that the phosphorylation status of p35 changes in a developmental manner. The phosphorylated from of p35 is resistant to cleavage by calpain and is more susceptible to proteasomal degradation. The unphosphorylated form of p35 is more resistant to proteasomal degradation but is more susceptible to calpain-dependent cleavage to produce p25. Autophosphorylation of p35 by Cdk5 suppresses the cleavage to p25 by calpain, whereas autophosphorylation facilitates the proteasomal degradation of p35. A phosphorylated form of p35 is more prevalent in the fetal brain, whereas the unphosphorylated form of p35 occurs in the adult brain. These results suggest that the autophosphorylation of p35 serves as a protective mechanism that suppresses the generation of p25 in developing brains.