RAB-10 regulates glutamate receptor recycling in a cholesterol-dependent endocytosis pathway
RAB-10 regulates glutamate receptor recycling in a cholesterol-dependent endocytosis pathway
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DOI：
10.1091/mbc.e07-05-0486
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发表时间：
2007-11-01
影响因子：
3.3
通讯作者：
Rongo, Christopher
中科院分区：
文献类型：
--
作者：
Glodowski, Doreen R.;Chen, Carlos Chih-Hsiung;Rongo, Christopher
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸型谷氨酸受体（AMPAR）的调节性内吞作用对突触可塑性至关重要。然而，在体内介导AMPAR运输的网格蛋白依赖性和非依赖性机制的特定组合尚未完全表征。在这里，我们研究的AMPAR亚基GLR-1在秀丽隐杆线虫的贩运。GLR-1位于突触膜上，在简单的行为回路中调节运动的逆转。缺乏RAB-10（一种肠内货物的内吞再循环所需的小GT酶）的动物在表型上与缺乏LIN-10（一种含有突触后密度95/盘-大/突触闭塞结构域的蛋白质）的动物相似：GLR-1在大的增生中积累，并且动物显示反转频率降低。unc-11（AP 180）或itsn-1（Intersectin 1）的突变，减少网格蛋白依赖性内吞作用，抑制lin-10，但不抑制rab-10突变表型，表明LIN-10在网格蛋白介导的内吞作用后发挥功能。相比之下，胆固醇耗竭，损害脂筏形成和网格蛋白独立的内吞作用，抑制rab-10，但不是lin-10表型，这表明RAB-10功能后网格蛋白独立的内吞作用。缺乏这两种基因的动物显示出额外的GLR-1运输缺陷。我们提出RAB-10和LIN-10沿着沿着不同的途径将AMPAR从细胞内的内体隔室再循环到突触，每个通路对胆固醇和网格蛋白介导的内吞机制具有不同的敏感性。
Regulated endocytosis of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) is critical for synaptic plasticity. However, the specific combination of clathrin-dependent and -independent mechanisms that mediate AMPAR trafficking in vivo have not been fully characterized. Here, we examine the trafficking of the AMPAR subunit GLR-1 in Caenorhabditis elegans. GLR-1 is localized on synaptic membranes, where it regulates reversals of locomotion in a simple behavioral circuit. Animals lacking RAB-10, a small GTPase required for endocytic recycling of intestinal cargo, are similar in phenotype to animals lacking LIN-10, a postsynaptic density 95/disc-large/zona occludens-domain containing protein: GLR-1 accumulates in large accretions and animals display a decreased frequency of reversals. Mutations in unc-11 (AP180) or itsn-1(Intersectin 1), which reduce clathrin-dependent endocytosis, suppress the lin-10 but not rab-10 mutant phenotype, suggesting that LIN-10 functions after clathrin-mediated endocytosis. By contrast, cholesterol depletion, which impairs lipid raft formation and clathrin-independent endocytosis, suppresses the rab-10 but not the lin-10 phenotype, suggesting that RAB-10 functions after clathrin-independent endocytosis. Animals lacking both genes display additive GLR-1 trafficking defects. We propose that RAB-10 and LIN-10 recycle AMPARs from intracellular endosomal compartments to synapses along distinct pathways, each with distinct sensitivities to cholesterol and the clathrin-mediated endocytosis machinery.