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首页> 外文期刊>The European Journal of Neuroscience >Mutation in hotfoot-4J mice results in retention of delta2 glutamate receptors in ER.
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Mutation in hotfoot-4J mice results in retention of delta2 glutamate receptors in ER.

机译：hotfoot-4J小鼠中的突变导致ER中保留了delta2谷氨酸受体。

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摘要

The orphan glutamate receptor delta2 is selectively expressed in Purkinje cells and plays a critical role in cerebellar function. Recently, the ataxia of hotfoot-4J (ho-4J) mice was shown to be caused by a 170-amino acid deletion in the N-terminal region of delta2 receptors. To understand delta2 receptor function, we characterized these mutant receptors (delta2ho) in Purkinje cells. Immunohistochemical staining showed that delta2ho receptors of the ho-4J homozygotes were abundantly expressed but localized to the Purkinje cell soma; in wild-type mice, delta2 receptors were predominantly present at distal dendrites of Purkinje cells. In addition, delta2ho receptors of the ho-4J mice were sensitive to endoglycosidase H, a finding suggesting that delta2ho receptors were not transported beyond the endoplasmic reticulum (ER) or cis-Golgi apparatus. To gain further insights into the mechanisms of this phenomenon, we characterized delta2ho receptors in transfected HEK293 cells. delta2ho receptors expressed in HEK293 cells were also sensitive to endoglycosidase H. Immunohistochemical staining showed that delta2ho receptors colocalized with proteins retained in the ER. Furthermore, delta2ho receptors were not labelled by membrane-impermeable biotinylation reagents. Coimmunoprecipitation assays showed that the intermolecular interaction of delta2ho receptors was significantly weaker than those of wild-type delta2 receptors, a finding suggesting that the ho-4J region is involved in oligomerization of delta2 receptors. Thus, delta2ho receptors were retained in the ER, probably by the quality control mechanism that detects unstable oligomers. We conclude that the absence of delta2 receptors on the cell surface by failed transport from the ER of Purkinje cells causes ataxia.
机译：孤儿谷氨酸受体delta2在浦肯野细胞中选择性表达，并在小脑功能中起关键作用。最近，显示出hotfoot-4J（ho-4J）小鼠的共济失调是由delta2受体N端区域的170个氨基酸缺失引起的。为了了解delta2受体的功能，我们在Purkinje细胞中表征了这些突变受体（delta2ho）。免疫组织化学染色显示ho-4J纯合子的delta2ho受体表达丰富，但位于Purkinje细胞体中。在野生型小鼠中，Purkinje细胞的远端树突主要存在delta2受体。此外，ho-4J小鼠的delta2ho受体对糖苷内切酶H敏感，这一发现表明delta2ho受体未转运至内质网（ER）或顺式高尔基体。为了进一步了解这种现象的机制，我们对转染的HEK293细胞中的delta2ho受体进行了表征。 HEK293细胞中表达的delta2ho受体也对糖苷内切酶H敏感。免疫组织化学染色显示delta2ho受体与保留在ER中的蛋白质共定位。此外，delta2ho受体未被膜不可渗透的生物素化试剂标记。免疫共沉淀实验表明，del2 2ho受体的分子间相互作用明显弱于野生型del2 2受体，这一发现表明ho-4J区参与了del2 2受体的寡聚化。因此，可能通过检测不稳定寡聚体的质量控制机制将δ2ho受体保留在ER中。我们得出的结论是，从Purkinje细胞的ER转运失败，细胞表面上没有delta2受体会导致共济失调。

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