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）中表现出明显的向内整流和高Ca^<2+>通透性，而在大多数神经元（I型神经元）中表现出向外整流和可忽略的Ca^<2+>通透性。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)大鼠海马切片中存在相当数量的II型神经元（占非锥体神经元的14.4%）。相比之下，大脑皮层的II型神经元数量很少（1.8%）。然而，在海马和新皮层中，都存在大量表达I型和II型AMPA受体的中间神经元。2)分子生物学研究表明，GluR2 AMPA受体亚基不组装在II型受体中。为了分析脑内II型和中间型神经元存在的分子基础，我们建立了单细胞水平GluR2亚基mRNA的绝对定量方法。3)关于II型AMPA受体的功能方面，我们已经证明它们参与海马和新皮层中大量非锥体神经元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，需要特异性影响该受体的药理学工具。我们发现合成蜘蛛毒素和1-萘酰乙酰精胺两种多胺衍生物选择性抑制II型AMPA受体，而对I型AMPA受体无影响。这些药物的作用高度依赖于电压。

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.