Mechanisms involved in the reduction of GABAA receptor α1-subunit expression caused by the epilepsy mutation A322D in the trafficking-competent receptor
Mechanisms involved in the reduction of GABAA receptor α1-subunit expression caused by the epilepsy mutation A322D in the trafficking-competent receptor
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DOI：
10.1074/jbc.m801708200
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发表时间：
2008-08-08
影响因子：
4.8
通讯作者：
Wang, Yu Tian
中科院分区：
文献类型：
--
作者：
Bradley, Clarrisa A.;Taghibiglou, Changiz;Wang, Yu Tian
GABA（A）Rs α 1亚基（A322D）突变导致一个加拿大大家族的青少年肌阵挛性癫痫先前的工作已经确定，该突变体影响HEK293细胞中表达的重组GABAAR的细胞表达和功能。在这里，我们已经扩展了这些观察结果表明，突变促进协会与内质网伴侣钙连接蛋白和加速降解速率的亚基类似的2.5倍。我们还发现，突变导致亚基降解主要是由溶酶体依赖的过程。此外，我们发现，突变的结果，在受体插入到质膜，但更迅速内吞的发动蛋白和小窝蛋白1依赖的机制。这些结果表明，突变亚基可以形成功能性受体，但这些受体在质膜上的寿命较短。
A mutation in the alpha 1-subunit (A322D) of GABA(A)Rs is responsible for juvenile myoclonic epilepsy in a large Canadian family. Previous work has identified that this mutant affects the cell expression and function of recombinant GABAARs, expressed in HEK293 cells. Here we have extended these observations by showing that the mutation promotes association with the endoplasmic reticulum chaperone calnexin and accelerates the degradation rate of the subunits similar to 2.5-fold. We also find that the mutation causes the subunit to be degraded largely by a lysosomal-dependent process. Furthermore, we find that the mutation results in receptors that are inserted into the plasma membrane but are more rapidly endocytosed by a dynamin and caveolin1-dependent mechanism. These results suggest that the mutant subunit can form functional receptors, but that these have a shorter lifetime on the plasma membrane.