Regulated lysosomal trafficking as a mechanism for regulating GABAA receptor abundance at synapses in Caenorhabditis elegans
Regulated lysosomal trafficking as a mechanism for regulating GABAA receptor abundance at synapses in Caenorhabditis elegans
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DOI：
10.1016/j.mcn.2010.04.002
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发表时间：
2010-08-01
影响因子：
3.5
通讯作者：
Bamber, Bruce A.
中科院分区：
文献类型：
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作者：
Davis, Kathleen M.;Sturt, Brianne L.;Bamber, Bruce A.
GABA（A）受体可塑性对正常脑功能和疾病进展都很重要。我们正在研究GABA（A）受体的可塑性在秀丽隐杆线虫使用的遗传方法。蠕虫急性暴露于GABA（A）激动剂蝇蕈醇会使突触后细胞超极化，导致瘫痪。几个小时后，蠕虫会适应，但表现出不协调的运动，这与GABA信号的减少一致。利用膜片钳和免疫荧光方法，我们发现GABA（A）受体在适应过程中被选择性地从突触中去除。亚单位mRNA水平不变，表明转录后机制。溶酶体功能缺陷的突变体（cup-5）在蝇蕈醇暴露前显示突触GABA（A）受体水平升高。在适应过程中，这些受体被更缓慢地去除，并在晚期内体标记物GFP-RAB-7阳性的细胞内细胞器中积累。这些发现表明，慢性激动剂暴露增加GABA（A）受体的内吞作用和溶酶体运输，导致突触GABA（A）受体水平降低和突触后GABA敏感性降低。(C)2010年爱思唯尔公司All rights reserved.
GABA(A) receptor plasticity is important for both normal brain function and disease progression. We are studying GABA(A) receptor plasticity in Caenorhabditis elegans using a genetic approach. Acute exposure of worms to the GABA(A) agonist muscimol hyperpolarizes postsynaptic cells, causing paralysis. Worms adapt after several hours, but show uncoordinated locomotion consistent with decreased GABA signaling. Using patch-clamp and immunofluorescence approaches, we show that GABA(A) receptors are selectively removed from synapses during adaptation. Subunit mRNA levels were unchanged, suggesting a post-transcriptional mechanism. Mutants with defective lysosome function (cup-5) show elevated GABA(A) receptor levels at synapses prior to muscimol exposure. During adaptation, these receptors are removed more slowly, and accumulate in intracellular organelles positive for the late endosome marker GFP-RAB-7. These findings suggest that chronic agonist exposure increases endocytosis and lysosomal trafficking of GABA(A) receptors, leading to reduced levels of synaptic GABA(A) receptors and reduced postsynaptic GABA sensitivity. (C) 2010 Elsevier Inc. All rights reserved.