The neurotoxin domoate causes long-lasting inhibition of the kainate receptor GluK5 subunit
The neurotoxin domoate causes long-lasting inhibition of the kainate receptor GluK5 subunit
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DOI：
10.1016/j.neuropharm.2014.05.003
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发表时间：
2014-10-01
影响因子：
4.7
通讯作者：
Fisher, Janet L.
中科院分区：
文献类型：
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作者：
Fisher, Janet L.
亲离子型谷氨酸受体（iGluRs）负责哺乳动物脑中的快速兴奋性神经传递，并且是神经元活动和突触可塑性的关键调节剂。三种主要类型的iGluR（AMPA、NMDA和红藻氨酸受体）由不同的亚基群体组成。四聚体红藻氨酸受体可以由五种不同类型的亚基（GluK 1-GluK 5）的组合组装而成。GluK 1 -3亚基能够产生功能性同源受体，而GluK 4 -5是专性异聚体，并且必须与GluK 1 -3亚基组装。神经毒素domoate被广泛用作红藻氨酸型受体的激动剂，因为与谷氨酸相比，它产生的脱敏反应较少。我们已经确定了一个额外的，亚基依赖性的行动domoate重组红藻氨酸受体。当应用于异聚体GluK 2/K5受体时，domoate产生小的，持久的，紧张性电流。此外，短暂暴露于domoate抑制GluK 5亚基，防止其被其他激动剂激活数分钟。这些特征与GluK 1、K2或K4亚基无关，可以通过GluK 5中降低激动剂结合亲和力的突变来预防。结果还表明，domoate结合，GluK 2/K5异聚体受体可以完全激活通过GluK 2亚基的激动剂，这表明在四聚体的亚基可以独立地发挥作用，打开离子通道，domoate结合状态是不是一个脱敏或阻断构象。这项研究描述了新的属性与domoate行动在红藻氨酸受体，并进一步表征不同的亚基在异聚体受体中发挥的不同作用。(C)2014爱思唯尔有限公司版权所有。
Ionotropic glutamate receptors (iGluRs) are responsible for fast excitatory neurotransmission in the mammalian brain, and are critical regulators of neuronal activity and synaptic plasticity. The three main types of iGluRs (AMPA, NMDA, and kainate receptors) are composed of distinct subunit populations. The tetrameric kainate receptors can be assembled from a combination of five different types of subunits (GluK1-GluK5). GluK1-3 subunits are able to produce functional homomeric receptors, while GluK4-5 are obligate heteromers, and must assemble with a, GluK1-3 subunit. The neurotoxin domoate is widely used as an agonist at kainate-type receptors because it produces a less desensitizing response compared to glutamate. We have identified an additional, subunit-dependent action of domoate at recombinant kainate receptors. When applied to heteromeric GluK2/K5 receptors, domoate generates a small, long-lasting, tonic current. In addition, brief exposure to domoate inhibits the GluK5 subunit, preventing its activation by other agonists for several minutes. These characteristics are not associated with the GluK1, K2, or K4 subunits and can be prevented by a mutation in GluK5 that reduces agonist binding affinity. The results also show that the domoate-bound, GluK2/K5 heteromeric receptors can be fully activated by agonists acting through the GluK2 subunit, suggesting that the subunits within the tetramer can function independently to open the ion channel, and that the domoate-bound state is not a desensitized or blocked conformation. This study describes new properties associated with domoate action at kainate receptors, and further characterizes the distinct roles played by different subunits in heteromeric receptors. (C) 2014 Elsevier Ltd. All rights reserved.