...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans
【24h】

Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans

机译：离子型AMPA受体3的突变会改变通道特性，并与人类中度认知障碍相关

获取原文
获取原文并翻译 | 示例
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (iGluRs) mediate the majority of excitatory synaptic transmission in the CNS and are essential for the induction and maintenance of long-term potentiation and long-term depression, two cellular models of learning and memory. We identified a genomic deletion (0.4 Mb) involving the entire GRIA3 (encoding iGluR3) by using an X-array comparative genomic hybridization (CGH) and four missense variants (G833R, M706T, R631S, and R450Q) in functional domains of iGluR3 by sequencing 400 males with X-linked mental retardation (XLMR). Three variants were found in males with moderate MR and were absent in 500 control males. Expression studies in HEK293 cells showed that G833R resulted in a 78% reduction of iGluR3 due to protein misfolding. Whole-cell recording studies of iGluR3 homomers in HEK293 cells revealed that neither iGluR3-M706T (S2 domain) nor iGluR3-R631S (near channel core) had substantial channel function, whereas R450Q (S1 domain) was associated with accelerated receptor desensitization. When forming heteromeric receptors with iGluR2 in HEK293 cells, all four iGluR3 variants had altered desensitization kinetics. Our study provides the genetic and functional evidence that mutant iGluR3 with altered kinetic properties is associated with moderate cognitive impairment in humans.
机译：离子型α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体（iGluRs）介导中枢神经系统的大多数兴奋性突触传递，对于诱导和维持长期的增强作用和长期的术语抑郁，学习和记忆的两种细胞模型。我们通过测序确定了涉及iGluR3功能域的X阵列比较基因组杂交（CGH）和四个错义变体（G833R，M706T，R631S和R450Q）的基因缺失（0.4 Mb）涉及整个GRIA3（编码iGluR3） 400名男性，患有X连锁智力障碍（XLMR）。在患有中度MR的男性中发现了三种变异，而在500名对照男性中则没有。在HEK293细胞中的表达研究表明，由于蛋白质错误折叠，G833R导致iGluR3降低了78％。在HEK293细胞中对iGluR3同聚物的全细胞记录研究表明，iGluR3-M706T（S2域）和iGluR3-R631S（近通道核心）都没有实质的通道功能，而R450Q（S1域）与受体脱敏加速有关。当在HEK293细胞中与iGluR2形成异源受体时，所有四个iGluR3变体均改变了脱敏动力学。我们的研究提供了遗传和功能证据，即动力学特性发生改变的突变体iGluR3与人类中度认知障碍有关。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号