Subunit-dependent modulation of kainate receptors by muscarinic acetylcholine receptors.
Subunit-dependent modulation of kainate receptors by muscarinic acetylcholine receptors.
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毒蕈碱乙酰胆碱受体对红藻氨酸受体的亚基依赖性调节。
DOI：
10.1016/j.brainres.2010.07.029
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发表时间：
2010
期刊：
影响因子：
2.9
通讯作者：
Mott,DavidD
中科院分区：
文献类型：
--
作者：
Benveniste,Morris;Wilhelm,Jennifer;Dingledine,RaymondJ;Mott,DavidD
胆碱能和多巴胺能神经递质系统之间的相互作用影响突触传递和可塑性。虽然之前的研究已经研究了乙酰胆碱（ACh）与NMDA或AMPA受体之间的串扰，但人们对ACh对红藻氨酸受体（KAR）的影响知之甚少。我们发现，刺激m1或m3毒蕈碱乙酰胆碱受体（mAChRs）2分钟增强重组KAR电流在一个持久的方式。毒蕈碱AChR激活增强异聚GluK 2/GluK 4和GluK 2/GluK 5受体，但不增强同聚GluK 2受体。在海马脑片中，红藻氨酸增强苔藓纤维轴突兴奋性。瞬时mAChR激活增强了红藻氨酸的这种作用，这表明乙酰胆碱可以调节海马中的突触传递的一种新机制。KAR过度活化与兴奋性毒性细胞死亡有关。为了确定mAChR和KAR之间相互作用的功能意义，我们研究了mAChR激活对KAR介导的兴奋性毒性的影响。我们发现，在药物阻断NMDA和AMPA受体，KAR激活AMPA产生显着的细胞死亡在原代皮层培养。伴刀豆球蛋白A（Con A），选择性地阻断KAR脱敏，显着增加这种KAR介导的神经毒性。毛果芸香碱短暂激活mAChRs显著增强了KAR介导的兴奋性毒性，无论是在存在还是不存在Con A的情况下。我们的结论是，KARs调制的亚基依赖的方式mAChRs。我们认为，乙酰胆碱可能会引起长期持久的神经元兴奋性的改变，并通过增强KAR功能的部分增强兴奋毒性。
Interactions between cholinergic and glutamatergic neurotransmitter systems influence synaptic transmission and plasticity. While previous studies have examined cross-talk between acetylcholine (ACh) and NMDA or AMPA receptors, little is known about the effect of ACh on kainate receptors (KARs). We show that stimulation of m1 or m3 muscarinic ACh receptors (mAChRs) for 2min potentiates recombinant KAR currents in a long lasting fashion. Muscarinic AChR activation potentiates heteromeric GluK2/GluK4 and GluK2/GluK5 receptors, but not homomeric GluK2 receptors. In hippocampal slices kainate potentiates mossy fiber axon excitability. Transient mAChR activation enhances this action of kainate, suggesting a novel mechanism through which acetylcholine could modulate synaptic transmission in the hippocampus. KAR over-activation has been implicated in excitotoxic cell death. To establish the functional significance of the interaction between mAChRs and KARs we examined the effect of mAChR activation on KAR-mediated excitotoxicity. We find that during pharmacological blockade of NMDA and AMPA receptors, KAR activation with AMPA produces significant cell death in primary cortical culture. Concanavalin A (Con A), which selectively blocks KAR desensitization, markedly increases this KAR-mediated neurotoxicity. Brief activation of mAChRs with pilocarpine significantly enhances KAR-mediated excitotoxicity both in the presence and absence of Con A. We conclude that KARs are modulated in a subunit dependent manner by mAChRs. We suggest that ACh may induce long lasting alterations in neuronal excitability and enhance excitotoxicity in part by potentiating KAR function.