• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >General anesthetics inhibit the neurotransmitter release machinery.
【24h】

General anesthetics inhibit the neurotransmitter release machinery.

机译：全身麻醉药会抑制神经递质的释放机制。

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

Despite their importance, the mechanism of action of general anesthetics is still poorly understood. Facilitation of inhibitory GABA A receptors plays an important role in anesthesia but other targets have also been linked to anesthetic actions. Anesthetics are known to suppress excitatory synaptic transmission, but it has been difficult to determine whether they act on the neurotransmitter release machinery itself. The data in the present work suggest that clinical concentrations of both intravenous and volatile general anesthetics are able to inhibit neurotransmitter release through one or more direct interactions with the mammalian neurotransmitter release machinery. Three main findings in this work point to this conclusion. First, the commonly used volatile anesthetic, isoflurane, as well as two commonly used intravenous anesthetics, propofol and etomidate, were found to significantly inhibit neurotransmitter release from digitonin-permeablized mammalian neurosecretory cells stimulated with a 100 muM Ca2+ solution. Dose-dependent inhibition of neurotransmitter release was observed with all three anesthetics and significant amounts of inhibition occurred throughout each anesthetic's clinically relevant concentration range. Furthermore, inhibition of neurotransmitter release in permeablized neurosecretory cells was specific to anesthetic producing compounds and was not observed in the presence of the nonimmobilizer, F6, the inactive propofol isomer, 2,4-diisopropophenol, or diazepam. Second, clinically relevant concentrations of isoflurane, propofol and etomidate inhibited vesicle fusion in cultured hippocampal neurons as evidenced by the fact that release of the styryl dye RH414, loaded into synaptic vesicles, was markedly reduced in the presence of these anesthetics following ionomycin treatment. Thus, both inhalational and intravenous anesthetics appear to inhibit the neurotransmitter release machinery in neurons found within the mammalian CNS. Finally, overexpression of a truncated form of the T-SNARE, syntaxin 1A, completely blocked isoflurane and propofol's ability to inhibit neurotransmitter release from permeablized PC12 cells. This mutant form of syntaxin, md130A, lacks its C-terminal transmembrane domain as well as a portion of its SNARE motif. Overexpession of md130A alone had no affect on evoked neurotransmitter release. Furthermore, overexpression of wild-type syntaxin had no effect on isoflurane or propofol's ability to inhibit neurotransmitter release from permeablized cells. This finding suggests, but does not prove, that syntaxin 1A may be an intermediary in isoflurane's and propofol's ability to inhibit neurotransmitter release in mammalian cells. Interestingly, overexpression of md130A was found to have no effect on etomidate's ability to inhibit neurotransmitter release from permeablized cells. While md130A overexpression did not block etomidate's inhibition of the neurotransmitter release machinery this does not necessarily exclude syntaxin as a candidate effector of etomidate. Nevertheless, etomidate's site of action on the neurotransmitter release machinery appears to be distinct from that of isoflurane and propofol.
机译：尽管具有重要意义，但对全身麻醉药的作用机理仍知之甚少。抑制性GABA A受体的促进在麻醉中起着重要作用，但其他目标也与麻醉作用有关。麻醉药可抑制兴奋性突触传递，但很难确定它们是否对神经递质释放机制本身起作用。目前工作中的数据表明，静脉内和全身麻醉药的临床浓度均能够通过与哺乳动物神经递质释放机制的一种或多种直接相互作用来抑制神经递质的释放。这项工作的三个主要发现指出了这一结论。首先，发现常用的挥发性麻醉药异氟烷以及两种常用的静脉麻醉药丙泊酚和依托咪酯能显着抑制用100μMCa2 +溶液刺激的经洋地黄素透化的哺乳动物神经分泌细胞的神经递质释放。在所有三种麻醉剂中均观察到神经递质释放的剂量依赖性抑制作用，并且在每种麻醉剂的临床相关浓度范围内均发生大量抑制作用。此外，在透化的神经分泌细胞中抑制神经递质的释放对麻醉剂具有特异性，在非固定剂F6，无活性的异丙酚异构体，2,4-二异丙酚或地西epa的存在下未观察到抑制作用。其次，临床相关浓度的异氟烷，异丙酚和依托咪酯抑制了培养的海马神经元中的囊泡融合，这是由离子霉素处理后这些麻醉剂的存在下负载在突触囊泡中的苯乙烯染料RH414的释放明显减少这一事实所证明的。因此，吸入麻醉药和静脉麻醉药似乎都抑制了哺乳动物CNS内神经元的神经递质释放机制。最后，截短形式的T-SNARE，syntaxin 1A的过表达完全阻断了异氟烷和异丙酚抑制透化PC12细胞释放神经递质的能力。语法蛋白md130A的这种突变形式缺少其C端跨膜结构域以及其SNARE主题的一部分。单独使用md130A的过量摄入对诱发的神经递质释放没有影响。此外，野生型语法蛋白的过表达对异氟烷或异丙酚抑制从透化细胞释放神经递质的能力没有影响。这一发现表明但没有证明语法1A可能是异氟烷和异丙酚抑制哺乳动物细胞中神经递质释放的能力的中介。有趣的是，发现md130A的过表达对依托咪酯抑制透化细胞释放神经递质的能力没有影响。尽管md130A的过表达并未阻止依托咪酯对神经递质释放机制的抑制，但这并不一定排除语法素作为依托咪酯的候选效应物。然而，依托咪酯在神经递质释放机制上的作用部位似乎与异氟烷和异丙酚不同。

著录项

  • 作者

    Herring, Bruce E.;

  • 作者单位

    The University of Chicago.;

  • 授予单位 The University of Chicago.;
  • 学科 Biology Neurobiology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 113 p.
  • 总页数 113
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 宗教;
  • 关键词

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