Ischemic insults direct glutamate receptor subunit 2-lacking AMPA receptors to synaptic sites
Ischemic insults direct glutamate receptor subunit 2-lacking AMPA receptors to synaptic sites
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DOI：
10.1523/jneurosci.0567-06.2006
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发表时间：
2006-05-17
影响因子：
5.3
通讯作者：
Wan, Qi
中科院分区：
文献类型：
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作者：
Liu, Baosong;Liao, Mingxia;Wan, Qi
兴奋性突触上的受调控AMPA受体（AMPAR）运输是突触功效活动依赖性改变的关键机制。然而，受调节的AMPAR运输在损伤诱导的突触重塑和/或细胞死亡中的作用尚不清楚。在这里，我们表明，短暂的氧-葡萄糖剥夺（OGD），脑缺血的体外模型，促进海马神经元突触的AMPAR的重新分配，导致AMPAR亚基组成的开关。缺血性损伤通过网格蛋白依赖性内吞作用促进含谷氨酸受体亚基2（GluR 2）的AMPAR从突触部位的内化，并通过可溶性N-乙基马来酰亚胺敏感因子附着蛋白受体依赖性胞吐作用促进GluR 2缺乏的AMPAR向突触部位的递送，这在损伤后早期是明显的。OGD诱导的受体亚基组成的转换需要PKC激活，GluR 2从AMPA受体结合蛋白的解离，以及与C激酶-1相互作用的蛋白的结合。我们进一步表明，AMPAR在突触的侮辱神经元表现出功能特性的GluR 2缺乏AMPAR。AMPAR介导的微型EPSC表现出增加的幅度和增强的敏感性，亚单位特异性阻断剂GluR 2缺乏AMPAR，缺血后24小时明显。OGD诱导的突触AMPA电流的改变需要网格蛋白介导的受体内吞作用和PKC激活。因此，缺血性损伤促进缺乏GluR 2的AMPAR靶向海马神经元的突触，其机制可能与缺血诱导的突触重塑和/或神经元死亡相关。
Regulated AMPA receptor (AMPAR) trafficking at excitatory synapses is a mechanism critical to activity-dependent alterations in synaptic efficacy. The role of regulated AMPAR trafficking in insult-induced synaptic remodeling and/or cell death is, however, as yet unclear. Here we show that brief oxygen-glucose deprivation (OGD), an in vitro model of brain ischemia, promotes redistribution of AMPARs at synapses of hippocampal neurons, leading to a switch in AMPAR subunit composition. Ischemic insults promote internalization of glutamate receptor subunit 2 (GluR2)-containing AMPARs from synaptic sites via clathrin-dependent endocytosis and facilitate delivery of GluR2-lacking AMPARs to synaptic sites via soluble N-ethylmaleimide-sensitive factor attachment protein receptor-dependent exocytosis, evident at early times after insult. The OGD-induced switch in receptor subunit composition requires PKC activation, dissociation of GluR2 from AMPA receptor-binding protein, and association with protein interacting with C kinase-1. We further show that AMPARs at synapses of insulted neurons exhibit functional properties of GluR2-lacking AMPARs. AMPAR-mediated miniature EPSCs exhibit increased amplitudes and enhanced sensitivity to subunit-specific blockers of GluR2-lacking AMPARs, evident at 24 h after ischemia. The OGD-induced alterations in synaptic AMPA currents require clathrin-mediated receptor endocytosis and PKC activation. Thus, ischemic insults promote targeting of GluR2-lacking AMPARs to synapses of hippocampal neurons, mechanisms that may be relevant to ischemia-induced synaptic remodeling and/or neuronal death.