摘 要：摘 要：大脑中神经元突触间的信号传递是由许多神经递质受体介导的。在过去，Richard L. Huganir实验室一直致力于神经递质受体功能调节的分子机制。而最近，该实验室又聚焦到大脑中一种最主要的兴奋性受体的研究——谷氨酸受体。谷氨酸受体主要可以分为两大类：AMPA受体和NMDA受体。AMPA受体主要介导了快速的兴奋性突触传递；而NMDA受体则在神经可塑性和发育中起到重要作用。实验发现，AMPA受体和NMDA受体都可以被一系列的蛋白激酶磷酸化，而磷酸化的水平则直接影响了这些受体的功能特性，包括通道电导和受体膜定位等。AMPA受体磷酸化的水平同时还在学习和记忆的细胞模型中发生改变，如长时程增强(LTP)和长时程抑制(LTD)。此外，AMPA受体中GluR1亚单位的磷酸化对于各种形式的可塑性以及空间记忆的维持有重要的作用。实验室主要研究突触部位谷氨酸受体在亚细胞水平的定位和聚集的分子机制。最近，一系列可以直接或间接与AMPA和NMDA受体相互作用的蛋白质得以发现，其中包括一个新发现的蛋白家族GRIPs (glutamate receptor interacting proteins)。GRIPs可以直接和AMPA受体的GluR2/3亚单位的C端结合。GRIPs包含7个PDZ结构域，可以介导蛋白与蛋白直接的相互连接，从而把各个AMPA受体交互连接在一起并与其他蛋白相连。另外，GluR2亚单位的C端还可以和兴奋性突触中的蛋白激酶C结合蛋白(PICK1)的PDZ结构域相互作用。另外，GluR2亚单位的C端也可以与一种参与膜融合的蛋白NSF相互作用。这些与AMPA受体相互作用的蛋白质对于受体在膜上的运输以及定位有至关重要的作用。同时，受体与PICK1和GRIP的结合对于小脑运动学习中的LTD有重要作用。 总体上说，该实验室发现了一系列可以调节神经递质受体功能的分子机制，这些工作提示受体功能的调节可能是突触传递可塑性发生的一个主要机制，并且可能最终导致了动物行为的改变。
关键词：神经递质受体；可塑性；磷酸化
中图分类号：R338 文献标识码：A
Abstract: Abstract: Neurotransmitter receptors mediate signal transduction at the postsynaptic membrane of synaptic connections between neurons in the nervous system. We have been studying the molecular mechanisms in the regulation of neurotransmitter receptor function. Recently we have focused on glutamate receptors, the major excitatory receptors in the brain. Glutamate receptors can be divided into two major classes: AMPA and NMDA receptors. Studies in our laboratory have found that both AMPA and NMDA receptors are multiply phosphorylated by a variety of protein kinases. Phosphorylation regulates several functional properties of these receptors including conductance and membrane targeting. Recent studies in our lab have demonstrated that the phosphorylation of AMPA receptors is regulated during cellular models of learning and memory such as long-term potentiation (LTP) and long-term depression (LTD). Moreover, phosphorylation of the AMPA receptor GluR1 subunit is required for the expression of these forms of plasticity and for the retention of spatial memory.
We have also been examining the mechanisms of the subcellular targeting and clustering of glutamate receptors at synapses. We have recently identified a variety of proteins that directly or indirectly interact with AMPA and NMDA receptors. We have found a novel family of proteins that we call GRIPs (Glutamate Receptor Interacting Proteins) that directly bind to the C-termini of the GluR2/3 subunits of AMPA receptors. In addition, we have found that the C-termini of GluR2 also interact with the PDZ domain of PICK1, a protein kinase C-binding protein that is found at excitatory synapses. The GluR2 subunit also interacts with the NSF protein, a protein involved in the regulation of membrane fusion events. These AMPA receptor interacting proteins are critical in the proper membrane trafficking and synaptic targeting of these receptors. We have recently shown that the binding of PICK1 and GRIP is required for a specific form of LTD in the cerebellum that is a cellular model for motor learning.
In summary, we have examined the molecular mechanisms underlying the regulation of neurotransmitter receptor function. Our studies have suggested that regulation of receptor function may be a major mechanism for the regulation of synaptic plasticity in the nervous system and may be an important determinant of animal behavior.
Key words: Neurotransmitter receptor; plasticity; phosphorylation
