Structural basis of PI(4,5)P2-dependent regulation of GluA1 by phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP5K2A).
Structural basis of PI(4,5)P2-dependent regulation of GluA1 by phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP5K2A).
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DOI：
10.1007/s00424-013-1424-8
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发表时间：
2014-10
影响因子：
4.5
通讯作者：
Strutz-Seebohm, Nathalie
中科院分区：
文献类型：
--
作者：
Seebohm, Guiscard;Wrobel, Eva;Pusch, Michael;Dicks, Markus;Terhag, Jan;Matschke, Veronika;Rothenberg, Ina;Ursu, Oana N.;Hertel, Fabian;Pott, Lutz;Lang, Florian;Schulze-Bahr, Eric;Hollmann, Michael;Stoll, Raphael;Strutz-Seebohm, Nathalie
关键词：
嗜离子性谷氨酸受体是中枢神经系统中最重要的兴奋性受体，其功能受损可导致多种神经系统疾病。在这里，我们发现谷氨酸诱导的电流在表达GluA1的卵母细胞中通过共表达精神分裂症相关磷酸肌肽激酶PIP5K2A而增加。这种效应是由于膜丰度增强，并被PIP5K2A的点突变（N251S）减弱。急性注射PIP5K2A的主要产物PI(4,5)P2后，GluA1电流增加。通过在人胚胎肾细胞中表达野生型和突变型PIP5K2A，我们能够提供PIP5K2A突变体激酶活性受损的证据。我们通过丙氨酸扫描确定了GluA1的K813-K823区域是PI(4,5)P2效应的关键区域，表明PI(4,5)P2与该区域结合。PIP条带分析显示PI(4,5)P2与c端GluA1肽结合。目前的观察结果揭示了GluA1调控的新机制。本文的在线版本（doi:10.1007/s00424-013-1424-8）包含补充材料，仅供授权用户使用。
Ionotropic glutamate receptors are the most important excitatory receptors in the central nervous system, and their impairment can lead to multiple neuronal diseases. Here, we show that glutamate-induced currents in oocytes expressing GluA1 are increased by coexpression of the schizophrenia-associated phosphoinositide kinase PIP5K2A. This effect was due to enhanced membrane abundance and was blunted by a point mutation (N251S) in PIP5K2A. An increase in GluA1 currents was also observed upon acute injection of PI(4,5)P2, the main product of PIP5K2A. By expression of wild-type and mutant PIP5K2A in human embryonic kidney cells, we were able to provide evidence of impaired kinase activity of the mutant PIP5K2A. We defined the region K813–K823 of GluA1 as critical for the PI(4,5)P2 effect by performing an alanine scan that suggested PI(4,5)P2 binding to this area. A PIP strip assay revealed PI(4,5)P2 binding to the C-terminal GluA1 peptide. The present observations disclose a novel mechanism in the regulation of GluA1. The online version of this article (doi:10.1007/s00424-013-1424-8) contains supplementary material, which is available to authorized users.
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影响因子：
7.3
作者：
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通讯作者：
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DOI：
10.1002/ajmg.b.30294
发表时间：
2006-04-05
影响因子：
2.8
作者：
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通讯作者：
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