PHOSPHORYLATION- REGULATION OF POST-SYNAPTIC STRUCTURES.

磷酸化-突触后结构的调节。

• 批准号: 6196367
• 负责人: MARIA A MORABITO
• 金额: $ 8.6万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-14 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6196367
• 关键词: NMDA receptors; cyclin dependent kinase; enzyme activity; laboratory mouse; membrane channels; neuroregulation; phosphorylation; site directed mutagenesis; synapses

DESCRIPTION (Verbatim from the Applicant's Abstract): Disruption of synaptic function has been implicated in a number of developmental disorders. Synapses are highly specialized dynamic structures, sites of presynaptic neurotransmitter release and postsynaptic responses. Several classes of molecules including kinases have been implicated in these processes, but additional studies are necessary to elucidate the complex series of events that result in normally functioning synapses. PSD-95 is a postsynaptic density protein that clusters K+ ion channels and NMDA receptors at synapses. The N-terminal domain of PSD-95 mediates its multimerization and is critical for channel clustering. This domain is phosphorylated by the p35-cdk5 kinase. Mice lacking p35 have an increased susceptibility to seizures and a diminished ability to recover from them compared to wild type. Preliminary studies revealed that p35-cdk5 kinase is present in the postsynaptic density fraction and that p35 null mice have abnormal aggregations of synaptic proteins. Furthermore, the p35-cdk5 kinase can phosphorylate PSD-95. Remarkably, phosphorylation by p35-cdk5 prevents the clustering of Shaker-type K+ channels by PSD-95 in heterologous cells. These findings strongly implicate the p35-cdk5 kinase in the regulation of synaptic assembly, stability and function. In addition, they have led to the hypothesis that the phosphorylation of PSD-95 by the p35-cdk5 kinase prevents the multimerization of PSD-95 which, consequently, affects the clustering of K+ channels and NMDA receptors. According to this hypothesis, p35-cdk5 plays an integral role in synaptic function by regulating the assembly of postsynaptic structures and thus allowing rapid alterations in their electrical/biochemical properties. The proposed studies aim to establish the function of p35-cdk5 regulation in the clustering of the receptor and the assembly of synaptic structures. They will certainly allow significant advancement in the understanding of structural plasticity of synapses and their malfunction.

描述（逐字从申请人的摘要中）：突触的中断 功能与许多发育障碍有关。突触 是高度专业的动态结构，突触前的位置 神经递质释放和突触后反应。几个类 包括激酶在内的分子已经与这些过程有关，但是 需要进行其他研究，以阐明复杂的事件系列 导致正常运作的突触。 PSD-95是突触后密度 将K+离子通道和NMDA受体聚集在突触处的蛋白质。这 PSD-95的N末端结构域介导了其多聚化，对 通道聚类。该结构域被p35-CDK5激酶磷酸化。老鼠 缺少p35的癫痫发作敏感性增加，并且有所减少 与野生型相比，从它们中恢复的能力。初步研究 揭示了p35-CDK5激酶存在于突触后密度分数中 p35无效小鼠具有突触蛋白异常的聚集。 此外，p35-CDK5激酶可以磷酸化PSD-95。值得注意的是 p35-cdk5磷酸化阻止了振动型K+通道的聚类 由PSD-95在异源细胞中。这些发现强烈暗示p35-cdk5 激酶在调节突触组件，稳定性和功能中。在 此外，它们导致了以下假设：PSD-95的磷酸化 p35-CDK5激酶可防止PSD-95的多聚化，因此 影响K+通道和NMDA受体的聚类。据此 假设，p35-CDK5通过调节在突触功能中起着不可或缺的作用 突触后结构的组装，从而允许快速改变 它们的电/生化特性。拟议的研究旨在建立 p35-CDK5调节在受体聚类中的功能和 突触结构的组装。他们肯定会允许重大 了解突触的结构可塑性及其的发展 故障。