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

我们大脑中的信息是由神经细胞网络处理的。突触是神经元的一个重要组成部分，它是相邻神经元之间进行交流的地方。神经递质受体蛋白存在于突触的膜上。它们在接收来自一个神经元的信息，然后在接收神经细胞中诱导反应方面起着关键作用。NMDA受体是一种兴奋性的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发挥着不可或缺的作用。有几种密切相关的NMDA受体。它们的药理特性不同；它们在神经元膜上的定位，即在突触上或靠近突触的地方，即所谓的突触外位置，以及它们在神经元细胞内激活的不同信号通路和反应。在与法国Daniel Choquet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各自的流动性不同。一种类型（NR1/NR2A受体）停留在突触内，而NR1/NR2B受体更具移动性，可以很容易地在突触和突触外位置之间移动。NMDA受体通过与支架蛋白家族PSD-95蛋白的结合而固定在突触上。由于观察到它们各自横向迁移的差异，表明NMDA受体亚型与PSD-95蛋白的相互作用不同。这种不同的相互作用对于神经元的正确功能至关重要，因为不同的细胞内信号通路似乎被突触受体和突触外受体激活；事实上，这些功能反应是截然相反的，要么导致程序性细胞死亡，如“细胞凋亡”，要么促进神经元细胞存活。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，探讨决定NMDA受体亚型是定向到突触还是定向到突触外位点的因素。了解这些过程可能有助于开发NMDA受体亚型靶向治疗。

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.