Galectin Modulation of Glutamate Receptors and Neuronal Function

描述(申请人提供)：本项目的目的是了解动物来源的凝集素在神经系统活动中的作用。脑神经元电活动的研究 Galectins是哺乳动物中的一个可溶性半乳糖苷结合蛋白家族，到目前为止主要关注它们如何影响神经发生或作为脑癌细胞的转移因子。然而，Galectins也已知是由成熟神经系统中的神经胶质细胞和神经元分泌的，因此可能在大脑功能中具有生理作用。我们假设Galectins通过树突棘的短期形态变化、突触可塑性的改变和神经元活性的降低来影响神经元的功能。这些活动是由包括ERK/MAPK在内的细胞内信号级联反应调节的。神经细胞膜上表达的完整蛋白通常含有糖链N-乙酰乳糖胺，这是复杂寡糖的一种常见的双糖成分，因此可以作为Galectin结合和信号分子交联的靶标，导致信号分子的激活和启动细胞内酶的级联。除了对神经元的作用外，Galectins还可以通过变构调节作用来理解N-聚糖与离子型谷氨酸受体(IGluR)功能的相关性。因此，拟议的项目将阐明Galectins如何影响神经元功能和生存能力，并将这些蛋白质用作重组iGluRs结构-功能研究中的糖特异性工具。在特定的目标1中，我们将检测Galectin对小鼠海马区神经传递和突触可塑性的影响。在特定目标2中的实验将检验Galectins通过细胞内激酶级联改变神经元结构可塑性的假设。最后，在具体目标3中，我们将确定Galectin对iGluRs的作用光谱及其分子基础。我们将探索Galectins的物理特性，以优化其对iGluRs的功能作用。这些研究将深入了解Galectins与神经元功能的相关性，这也将有助于理解Galectins对胶质瘤诱导的神经元兴奋性改变的重要性。

DESCRIPTION (provided by applicant): The purpose of this project is to understand the role of animal-derived lectins in nervous system activity. Investigation into the neuronal activities of galectins, a family of mammalian soluble galactoside-binding proteins, thus far has focused primarily on how they impact neurogenesis or act as metastatic factors for brain cancer cells. However, galectins also are known to be secreted by glia and neurons in the mature nervous system, and therefore are likely to have a physiological role in brain function. We hypothesize that galectins impact neuronal function through short-term morphological changes in dendritic spines, alterations in synaptic plasticity, and reductions in neuronal viability. These activities re mediated by engagement of intracellular signaling cascades that include ERK/MAPK. Integral proteins expressed on neuronal plasma membranes typically contain the glycan N acetyllactosamine, a common disaccharide constituent of complex oligosaccharides, and therefore could serve as targets for galectin binding and cross-linking of signaling molecules, leading to their activation and initiation of intracellular enzymatic cascades. In addition to thei actions on neurons, galectins are useful tools for understanding the relevance of N-glycans to ionotropic glutamate receptor (iGluR) function due to their allosteric modulatory actions. Accordingly, the proposed project will elucidate how galectins impact neuronal function and viability and use these proteins as glycan-specific tools in structure-function studies with recombinant iGluRs. In Specific Aim 1, we will examine galectin activity on neurotransmission and synaptic plasticity in the mouse hippocampus. Experiments in Specific Aim 2 will test the hypothesis that galectins alter neuronal structural plasticity through intracellular kinase cascades. Finally, in Specific Aim 3, we will determine the spectrum of galectin actions on iGluRs and their molecular basis. We will probe the physical characteristics of galectins that optimize their functional action on iGluRs. These studies will yield insight into the as-yet unexplored relevance of galectins to neuronal function, which also will be relevant to understanding their importance to glioma-induced alterations in neuronal excitability.