...
  • 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 >Altered kinetics and benzodiazepine sensitivity of a GABA_A receptor subunit mutation [γ_2(R43Q)] found in human epilepsy
【24h】

Altered kinetics and benzodiazepine sensitivity of a GABA_A receptor subunit mutation [γ_2(R43Q)] found in human epilepsy

机译：在人类癫痫中发现的GABA_A受体亚基突变[γ_2（R43Q）]的动力学和苯二氮卓敏感性变化

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

The γ-aminobutyric acid type A (GABA_A) receptor mediates fast inhibitory synaptic transmission in the CNS. Dysfunction of the GABA_A receptor would be expected to cause neuronal hyperexcit-ability, a phenomenon linked with epileptogenesis. We have investigated the functional consequences of an arginine-to-glutamine mutation at position 43 within the GABA_A γ_2-subunit found in a family with childhood absence epilepsy and febrile seizures. Rapid-application experiments performed on receptors expressed in HEK-293 cells demonstrated that the mutation slows GABA_A receptor deactivation and increases the rate of desensiti-zation, resulting in an accumulation of desensitized receptors during repeated, short applications. In Xenopus Iaevis oocytes, two-electrode voltage-clamp analysis of steady-state currents obtained from α_1β_2γ_2 or α_1β_2γ_2(R43Q) receptors did not reveal any differences in GABA sensitivity. However, differences in the benzodiazepine pharmacology of mutant receptors were apparent. Mutant receptors expressed in oocytes displayed reduced sensitivity to diazepam and flunitrazepam but not the imidazopyridine zolpidem. These results provide evidence of impaired GABA_A receptor function that could decrease the efficacy of transmission at inhibitory synapses, possibly generating a hyperexcitable neuronal state in thalamocortical networks of epileptic patients possessing the mutant subunit.
机译：γ-氨基丁酸A型（GABA_A）受体介导中枢神经系统的快速抑制性突触传递。预期GABA_A受体功能异常会导致神经元过度兴奋，这是与癫痫发生有关的现象。我们调查了在一个患有儿童期癫痫和高热惊厥的家庭中发现的GABA_Aγ_2-亚基中第43位的精氨酸-谷氨酰胺突变的功能后果。对HEK-293细胞中表达的受体进行的快速应用实验表明，该突变减缓了GABA_A受体的失活并提高了脱敏率，导致脱敏受体在反复短暂应用中积累。在非洲爪蟾卵母细胞中，从α_1β_2γ_2或α_1β_2γ_2（R43Q）受体获得的稳态电流的两电极电压钳分析未显示GABA敏感性的任何差异。但是，突变受体的苯二氮卓药理学差异是显而易见的。在卵母细胞中表达的突变受体对地西epa和氟硝西epa的敏感性降低，但对咪唑并吡啶唑吡坦却没有。这些结果提供了GABA_A受体功能受损的证据，该功能可能降低抑制性突触的传递功效，并可能在拥有突变亚基的癫痫患者的丘脑皮质网络中产生超兴奋性神经元状态。

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