PICK1-mediated glutamate receptor subunit 2 (GluR2) trafficking contributes to cell death in oxygen/glucose-deprived hippocampal neurons.
PICK1-mediated glutamate receptor subunit 2 (GluR2) trafficking contributes to cell death in oxygen/glucose-deprived hippocampal neurons.
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DOI：
10.1074/jbc.m901203200
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发表时间：
2009-05-22
期刊：
影响因子：
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通讯作者：
Hanley JG
中科院分区：
文献类型：
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作者：
Dixon RM;Mellor JR;Hanley JG
氧和葡萄糖剥夺（OGD）通过Ca 2 +/Zn 2+可渗透的、GluR 2缺乏的AMPA受体（AMPAR）诱导海马CA 1区神经元延迟性细胞死亡。OGD后，海马神经元中的突触AMPAR电流显示出显著的内向整流和对GluR 2缺乏AMPAR的通道阻断剂选择性的敏感性增加。这通过两种机制发生：延迟下调GluR 2 mRNA的表达和快速内化的GluR 2-含有AMPAR在OGD损伤，这是取代GluR 2缺乏受体。亚基组成快速变化的机制尚不清楚。在这里，我们表明，这种贩运事件的共同特点与事件介导的长期抑郁症和长期增强，并启动了N-甲基-D-天冬氨酸受体的激活。使用生物化学和电生理学的方法，我们表明，肽干扰PICK 1 PDZ结构域的相互作用，阻止OGD诱导的开关的亚基组成，牵连PICK 1限制GluR 2从突触OGD。此外，我们表明，GluR 2缺乏AMPAR，在OGD过程中出现的突触PICK 1 PDZ相互作用的结果参与OGD诱导的延迟细胞死亡。这项工作表明，PICK 1在对OGD的反应中起着至关重要的作用，导致突触传递和神经元死亡的改变，并对我们理解中风期间细胞死亡的分子机制产生影响。
Oxygen and glucose deprivation (OGD) induces delayed cell death in hippocampal CA1 neurons via Ca2+/Zn2+-permeable, GluR2-lacking AMPA receptors (AMPARs). Following OGD, synaptic AMPAR currents in hippocampal neurons show marked inward rectification and increased sensitivity to channel blockers selective for GluR2-lacking AMPARs. This occurs via two mechanisms: a delayed down-regulation of GluR2 mRNA expression and a rapid internalization of GluR2-containing AMPARs during the OGD insult, which are replaced by GluR2-lacking receptors. The mechanisms that underlie this rapid change in subunit composition are unknown. Here, we demonstrate that this trafficking event shares features in common with events that mediate long term depression and long term potentiation and is initiated by the activation of N-methyl-d-aspartic acid receptors. Using biochemical and electrophysiological approaches, we show that peptides that interfere with PICK1 PDZ domain interactions block the OGD-induced switch in subunit composition, implicating PICK1 in restricting GluR2 from synapses during OGD. Furthermore, we show that GluR2-lacking AMPARs that arise at synapses during OGD as a result of PICK1 PDZ interactions are involved in OGD-induced delayed cell death. This work demonstrates that PICK1 plays a crucial role in the response to OGD that results in altered synaptic transmission and neuronal death and has implications for our understanding of the molecular mechanisms that underlie cell death during stroke.