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Functional significance of Ca^<2+>-permeable AMPA-type glutamate receptors in the central nervous system.

Ca ^ 2 -可渗透的AMPA型谷氨酸受体在中枢神经系统中的功能意义。

基本信息

批准号：
08458265
负责人：
OZAWA Seiji
金额：
$ 4.8万
依托单位：
Gunma University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1996
资助国家：
日本
起止时间：
1996 至 1997
项目状态：
已结题

项目摘要

AMPA receptors exhibit a marked inward rectification and high Ca^<2+> permeability in a population of cultured rat hippocampal neurons (type II neurons), whereas they exhibit an outwardly rectifying and negligible Ca^<2+> permeability in the majority of neurons (type I neurons). The receptors expressed in type I and type II neurons were designated as type I and type II AMPA receptors, respectively. The purposes of this study were to investigate the distribution of neurons with type II AMPA receptors and to elucidate their functional significances. The results are summarized as follows : 1) A considerable number of type II neurons were found in rat hippocampal slices (14.4% of nonpyramidal neurons). In contrast, the population of type II neurons was quite small in the cerebral cortex (1.8%). In both the hippocampus and the neocortex, however, there were a large number of intermediate neurons that expressed both type I and type II AMPA receptors. 2) Molecular biological studies have indicated that the GluR2 AMPA receptor subunit is not assembled in type II receptors. To analyze molecular basis of the presence of type II and intermediate neurons in the brain, we have established a method for absolute quantification of mRNA of GluR2 subunit at the single cell level. 3) Regarding the functional aspect of type II AMPA receptors, we have shown that they are involved in the fast excitatory neurotransmission in a large number of nonpyramidal neurons in both the hippocampus and the neocortex. 4) To further investigate functional roles of the type II AMPA receptor, pharmacological tools that specifically affect this receptor are needed. We have found that two polyamine derivatives, synthetic joro spider toxin and 1-naphthyl acetyl spermine, selectively suppress type II AMPA receptors with no effect on type I receptors. The dffects of these agents were highly voltage-dependent.

在培养的大鼠海马神经元(II型神经元)中，AMPA受体表现出明显的内向整流和高钙通透性，而在大多数神经元(I型神经元)中，AMPA受体表现出向外整流和可忽略的钙通透性。表达于I型和II型神经元的受体分别命名为I型和II型AMPA受体。本研究的目的是研究具有II型AMPA受体的神经元的分布，并阐明其功能意义。结果如下：1)在大鼠海马片中发现了相当数量的II型神经元(占非锥体神经元的14.4%)。相比之下，大脑皮层中II型神经元的数量很少(1.8%)。然而，在海马和新皮质中，都有大量的中间神经元同时表达I型和II型AMPA受体。2)分子生物学研究表明，GluR2 AMPA受体亚单位不能组装在II型受体上。为了分析大脑中存在II型神经元和中间神经元的分子基础，我们建立了一种在单细胞水平上绝对定量GluR2亚单位mRNA的方法。3)在AMPA受体的功能方面，我们已经证明它们参与了海马区和大脑皮层中大量非锥体细胞的快速兴奋性神经传递。4)为了进一步研究II型AMPA受体的功能作用，需要专门影响该受体的药理学工具。我们发现两种多胺衍生物，合成的若罗蜘蛛毒素和1-萘乙酰精胺，选择性地抑制II型AMPA受体，而对I型受体没有影响。这些药剂的作用高度依赖于电压。