A mosaic of functional kainate receptors in hippocampal interneurons
A mosaic of functional kainate receptors in hippocampal interneurons
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DOI：
10.1523/jneurosci.2156-04.2004
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发表时间：
2004-10-13
影响因子：
5.3
通讯作者：
Lerma, J
中科院分区：
文献类型：
--
作者：
Christensen, JK;Paternain, AV;Lerma, J
尽管红藻氨酸受体(KARs)的一些生理功能仍不清楚，但最近的研究进展突显了它在突触生理学中的作用。在海马片上，红藻氨酸抑制了GABA介导的突触抑制，增加了中间神经元的放电频率。然而，这些反应对激动剂的敏感性不同，这表明突触前KAR和躯体KAR具有不同的分子组成。海马区中间神经元表达几个不同的KAR亚基，它们可以组装成具有各种药理特性的异构体受体，原则上可以发挥不同的作用。为了说明哪些受体类型在中间神经元中介导了红藻氨酸的每一种效应，我们使用了新的化合物和缺乏特定KAR亚单位的小鼠。在重组实验中，5-羧基-2，4-二苯甲酰胺苯甲酸(NS3763)仅作用于谷氨酸受体亚基5(GluR5)，而3S，4AR，6S，8AR-6-((4-羧基苯基)甲基)1，2，3，4，4a，5，6，7，8，8a-十氢异喹啉-3-羧酸(LY382884)拮抗均聚体GluR5和任何含有GluR5亚基的异构体组合。在海马片上，LY382884能阻止红藻氨酸诱导的IPSC抑制，而NS3763不能。相反，这两种方法都没有阻止伴随而来的自发ipsc频率的增加。这些化合物的选择性在基因敲除小鼠中也被发现，因此它们在GluR5(-/-)小鼠中不起作用，但在GluR6(-/-)小鼠中完全有效。我们的数据表明，在野生型小鼠的CA1中间神经元中，它们的体室表达异构体GluR6-Ka2受体，在突触前终末表达GluR5-GluR6或GluR5-Ka2。然而，功能代偿似乎发生在零突变体中，一种新的药理学特征出现，与两个区段中的同源受体的活性更相容：GluR6(-/-)小鼠的GluR5和GluR5(-/-)小鼠的GluR6。
Although some physiological functions of kainate receptors (KARs) still remain unclear, recent advances have highlighted a role in synaptic physiology. In hippocampal slices, kainate depresses GABA-mediated synaptic inhibition and increases the firing rate of interneurons. However, the sensitivity to agonists of these responses differs, suggesting that the presynaptic and somatic KARs have a distinct molecular composition. Hippocampal interneurons express several distinct KAR subunits that can assemble into heteromeric receptors with a variety of pharmacological properties and that, in principle, could fulfill different roles. To address which receptor types mediate each of the effects of kainate in interneurons, we used new compounds and mice deficient for specific KAR subunits. In a recombinant assay, 5-carboxyl-2,4-di-benzamido-benzoic acid (NS3763) acted exclusively on homomeric glutamate receptor subunit 5 (GluR5), whereas 3S, 4aR, 6S, 8aR-6-((4-carboxyphenyl) methyl) 1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (LY382884) antagonized homomeric GluR5 and any heteromeric combination containing GluR5 subunits. In hippocampal slices, LY382884, but not NS3763, was able to prevent kainate-induced depression of evoked IPSC. In contrast, neither prevented the concomitant increase in spontaneous IPSC frequency. The selectivity of these compounds was seen additionally in knock-out mice, such that they were inactive in GluR5(-/-) mice but completely effective in GluR6(-/-) mice. Our data indicate that in wild-type mice, CA1 interneurons express heteromeric GluR6 - KA2 receptors in their somatic compartments and GluR5 - GluR6 or GluR5 - KA2 at presynaptic terminals. However, functional compensation appears to take place in the null mutants, a new pharmacological profile emerging more compatible with the activity of homomeric receptors in both compartments: GluR5 in GluR6(-/-) mice and GluR6 in GluR5(-/-) mice.