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

AMPA受体在培养的大鼠海马神经元（II型神经元）中表现出明显的内向整流和高Ca^2+渗透性，而在大多数神经元（I型神经元）中表现出外向整流和可忽略的Ca^2+渗透性。在I型和II型神经元中表达的受体分别被指定为I型和II型AMPA受体。本研究的目的是研究Ⅱ型AMPA受体神经元的分布及其功能意义。结果表明：（1）大鼠海马脑片中含有大量的Ⅱ型神经元，占非锥体神经元的14.4%。相比之下，II型神经元的人口是相当小的大脑皮层（1.8%）。然而，在海马和新皮层中，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，GluR 2 AMPA受体亚基不组装在II型受体。为了分析脑中II型和中间神经元存在的分子基础，我们建立了一种在单细胞水平上绝对定量GluR 2亚基mRNA的方法。3)关于II型AMPA受体的功能方面，我们已经表明，他们参与了大量的非锥体神经元在海马和新皮层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。我们已经发现两种多胺衍生物，合成的霍洛蜘蛛毒素和1-萘基乙酰精胺，选择性抑制II型AMPA受体，对I型受体没有影响。这些药物的作用具有高度的电压依赖性。

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.