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An investigation into NMDA receptor subtype synaptic targeting and lateral mobility mediated by the PSD-95 MAGUK family of scaffold proteins

对 PSD-95 MAGUK 支架蛋白家族介导的 NMDA 受体亚型突触靶向和横向移动性的研究

基本信息

批准号：
BB/G003718/1
负责人：
Frances Stephenson
金额：
$ 48.36万
依托单位：
University College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2008
资助国家：
英国
起止时间：
2008 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FG003718%2F1
关键词：
investigation into NMDA receptor subtype

项目摘要

Information in our brains is processed by a network of nerve cells. An important sub-component of a neurone is the synapse which is where communication between adjacent neurones occurs. Neurotransmitter receptor proteins are found in the membrane at the synapse. They are pivotal in receiving the message from one neurone and then inducing a response in the recipient nerve cell. NMDA receptors are a type of excitatory, glutamate neurotransmitter receptor. They play an integral role in memory formation and in neurological diseases such as schizophrenia, stroke, epilepsy and chronic pain. There are several types of closely related NMDA receptors. These differ with respect to their pharmacological properties; where they are localized in the neuronal membrane, i.e whether at synapses or close to the synapse in what are termed extra-synaptic sites and, in the different signalling pathways and responses they activate inside the neuronal cell. In collaboration with Dr Daniel Choquet's research group in France, we have recently discovered that NMDA receptor subtypes differ in their respective mobilities in neuronal membranes. One type (NR1/NR2A receptors) stays within the synapse whereas NR1/NR2B receptors are more mobile and can readily move between synaptic and extra-synaptic sites. NMDA receptors are anchored at synapses by their association with a family of scaffolding proteins, the PSD-95 proteins. Because of the observed differences in their respective lateral mobilities, it is suggested that NMDA receptor subtypes interact differently with the PSD-95 proteins. This differential interaction is crucial for the correct functioning of the neurones since different intracellular signalling pathways appear to be activated by synaptic versus extra-synaptic receptors; in fact these functional responses are diametrically opposed leading to either programmed cell death as in 'apoptosis' or in the promotion of neuronal cell survival. This research proposal aims to investigate the factors that determine whether an NMDA receptor subtype is directed to synapses or to extra-synaptic sites by studying the interaction of NMDA receptor subtypes and the scaffolding family of proteins, the PSD-95 proteins. Understanding these processes may contribute towards the development of NMDA receptor subtype targeted therapies.

我们大脑中的信息是由神经细胞网络处理的。神经元的一个重要的子组成部分是突触，它是相邻神经元之间进行通信的地方。神经递质受体蛋白质存在于突触的膜中。它们在接收来自一个神经元的信息，然后诱导受体神经细胞的反应中起着关键作用。NMDA受体是一种兴奋性谷氨酸神经递质受体。它们在记忆形成和精神分裂症、中风、癫痫和慢性疼痛等神经系统疾病中起着不可或缺的作用。有几种类型的密切相关的NMDA受体。它们的药理学性质不同;它们位于神经元膜中，即在突触处或靠近突触的所谓突触外位点，以及它们在神经元细胞内激活的不同信号传导途径和反应。在与法国丹尼尔·乔凯博士的研究小组合作中，我们最近发现NMDA受体亚型在神经元膜中的迁移率不同。一种类型（NR 1/NR 2A受体）停留在突触内，而NR 1/NR 2B受体更移动的，并且可以容易地在突触和突触外位点之间移动。NMDA受体通过与支架蛋白家族PSD-95蛋白的结合而锚定在突触处。由于观察到的差异，它们各自的横向迁移率，这表明，NMDA受体亚型与PSD-95蛋白的相互作用不同。这种差异的相互作用是至关重要的神经元的正确运作，因为不同的细胞内信号通路似乎被激活的突触与突触外受体;事实上，这些功能反应是截然相反的导致程序性细胞死亡，如在'凋亡'或在促进神经元细胞的存活。本研究计划旨在通过研究NMDA受体亚型与支架蛋白家族PSD-95蛋白的相互作用，研究决定NMDA受体亚型是否指向突触或突触外位点的因素。了解这些过程可能有助于NMDA受体亚型靶向治疗的发展。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Foreword: trafficking, assembly and regulation of neurotransmitter receptors and ion channels.

前言：神经递质受体和离子通道的运输、组装和调节。

DOI：
10.1080/09687680802060665
发表时间：
2008
期刊：
Molecular membrane biology
影响因子：
0
作者：
Stephenson FA
通讯作者：
Stephenson FA

Identification of C-Terminal Binding Protein 1 as a Novel NMDA Receptor Interactor.

DOI：
10.1007/s11064-018-2633-5
发表时间：
2019-06
期刊：
Neurochemical research
影响因子：
4.4
作者：
Cousins SL;Stephenson FA
通讯作者：
Stephenson FA

Organization of NMDA receptors at extrasynaptic locations.

DOI：
10.1016/j.neuroscience.2010.01.022
发表时间：
2010-04-28
期刊：
NEUROSCIENCE
影响因子：
3.3
作者：
Petralia, R. S.;Wang, Y. X.;Hua, F.;Yi, Z.;Zhou, A.;Ge, L.;Stephenson, F. A.;Wenthold, R. J.
通讯作者：
Wenthold, R. J.

Introduction to thematic minireview series on celebrating the discovery of the cysteine loop ligand-gated ion channel superfamily.

介绍庆祝发现半胱氨酸环配体门控离子通道超家族的主题迷你评论系列。