The potassium channel Kir4.1 associates with the dystrophin-glycoprotein complex via α-syntrophin in glia
The potassium channel Kir4.1 associates with the dystrophin-glycoprotein complex via α-syntrophin in glia
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DOI：
10.1074/jbc.m402604200
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发表时间：
2004-07-02
影响因子：
4.8
通讯作者：
Kofuji, P
中科院分区：
文献类型：
--
作者：
Connors, NC;Adams, ME;Kofuji, P
神经胶质细胞中钾通道的主要生理作用之一是促进中枢神经系统的“钾空间缓冲”，这是维持细胞外环境中最佳钾浓度所必需的过程。这一过程需要在神经胶质细胞膜的离散亚区高密度积累的钾离子通道的精确分布。为了更好地了解神经胶质细胞如何选择性地将钾通道靶向到离散的膜亚域，我们解决了神经胶质内纠偏钾通道Kir4.1是否与肌营养不良蛋白-糖蛋白复合物（DGC）相关的问题。免疫沉淀实验显示，Kir4.1与小鼠大脑和培养的皮质星形胶质细胞的DGC有关。体外免疫沉淀和下拉实验表明，Kir4.1可以直接结合α -syntrophin，这需要通道的最后三个氨基酸（SNV）的存在，这是一个一致的PDZ结构域结合基序。此外，Kir4.1不能与α -syntrophin敲除小鼠大脑中的DGC结合。这些结果表明，Kir4.1通过PDZ结构域介导的与α -syntrophin的相互作用与DGC相关联，定位于胶质细胞中，并提示DGC在中枢神经系统生理中起重要作用。
One of the major physiological roles of potassium channels in glial cells is to promote "potassium spatial buffering" in the central nervous system, a process necessary to maintain an optimal potassium concentration in the extracellular environment. This process requires the precise distribution of potassium channels accumulated at high density in discrete subdomains of glial cell membranes. To obtain a better understanding of how glial cells selectively target potassium channels to discrete membrane subdomains, we addressed the question of whether the glial inwardly rectifying potassium channel Kir4.1 associates with the dystrophin-glycoprotein complex (DGC). Immunoprecipitation experiments revealed that Kir4.1 is associated with the DGC in mouse brain and cultured cortical astrocytes. In vitro immunoprecipitation and pull-down assays demonstrated that Kir4.1 can bind directly to alpha-syntrophin, requiring the presence of the last three amino acids of the channel (SNV), a consensus PDZ domain-binding motif. Furthermore, Kir4.1 failed to associate with the DGC in brains from alpha-syntrophin knockout mice. These results suggest that Kir4.1 is localized in glial cells by its association with the DGC through a PDZ domain-mediated interaction with alpha-syntrophin and suggest an important role for the DGC in central nervous system physiology.