The adhesion molecule CHL1 regulates uncoating of clathrin-coated synaptic vesicles
The adhesion molecule CHL1 regulates uncoating of clathrin-coated synaptic vesicles
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DOI：
10.1016/j.neuron.2006.10.020
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发表时间：
2006-12-21
期刊：
影响因子：
16.2
通讯作者：
Schachner, Melitta
中科院分区：
文献类型：
--
作者：
Leshchyns'ka, Iryna;Sytnyk, Vladimir;Schachner, Melitta
在寻找免疫球蛋白超家族粘附分子CHL 1的细胞内结构域的结合伴侣时，我们确定了网格蛋白未涂层ATP酶Hsc 70。CHL 1基因消融导致Hsc 70对突触质膜和突触囊泡的靶向减少，表明CHL 1是Hsc 70的突触靶向线索。CHL 1在突触前膜中积累，并且响应于突触激活，通过内吞作用靶向于突触囊泡。CHL 1缺陷或CHL 1/Hsc 70复合物的破坏导致异常高水平的网格蛋白包被的突触囊泡的积累，其释放网格蛋白的能力降低。当CHL 1/Hsc 70复合物被破坏时，以活性依赖性方式产生的新网格蛋白包被的突触囊泡会受到抑制，导致突触终扣中FM染料的吸收和释放受损。因此，网格蛋白依赖性突触囊泡再循环的异常可能是携带CHL 1基因突变的人类和小鼠大脑功能障碍的基础。
In searching for binding partners of the intracellular domain of the immunoglobulin superfamily adhesion molecule CHL1, we identified the clathrin-uncoating ATPase Hsc70. CHL1 gene ablation resulted in reduced targeting of Hsc70 to the synaptic plasma membrane and synaptic vesicles, suggesting CHL1 as a synapse-targeting cue for Hsc70. CHL1 accumulates in presynaptic membranes and, in response to synapse activation, is targeted to synaptic vesicles by endocytosis. CHL1 deficiency or disruption of the CHL1/Hsc70 complex results in accumulation of abnormally high levels of clathrin-coated synaptic vesicles with a reduced ability to release clathrin. Generation of new clathrin-coated synaptic vesicles in an activity-dependent manner is inhibited when the CHL1/Hsc70 complex is disrupted, resulting in impaired uptake and release of FM dyes in synaptic boutons. Abnormalities in clathrin-dependent synaptic vesicle recycling may thus underlie brain malfunctions in humans and mice that carry mutations in the CHL1 gene.