Determinants of the Sensitivity of AMPA Receptors to Xenon
Determinants of the Sensitivity of AMPA Receptors to Xenon
复制标题
AMPA 受体对氙气敏感性的决定因素
作者：
A. Plested;S. Wildman;W. R. Lieb;N. Franks
背景关于全身麻醉剂对各种神经递质门控离子通道的作用，有大量且不断增加的文献，其中最受关注的是抑制性氨基丁酸A型受体。相比之下，谷氨酸受体，最重要的一类快速兴奋性神经递质门控受体通道，受到的关注要少得多，它们在麻醉状态的产生中的作用仍然存在争议。方法在非洲爪蟾卵母细胞和HEK-293细胞中表达由多种不同亚基形成的氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体，并使用双电极电压钳和膜片钳技术测定其对吸入性全身麻醉药氙、异氟醚和氟烷的敏感性。应用环噻嗪和定点突变技术研究脱敏对麻醉药敏感性的影响。超快速应用系统也被用来模拟快速高浓度谷氨酸释放在突触。结果采用海人藻酸盐浴法测定氙对AMPA受体有明显的抑制作用。然而，当天然神经递质l-谷氨酸在受体脱敏被阻断并且谷氨酸激活反应的峰值可以精确测量的条件下使用时，抑制模式发生显著变化。当脱敏被单点突变（GluR 1中的L497 Y和GluR 4中的等效突变L505 Y）消除时，氙抑制被消除。当使用模拟突触条件的超快速应用系统通过谷氨酸激活AMPA受体时，对氙、氟烷和异氟烷的敏感性可以忽略不计。结论AMPA受体，在异源表达系统中进行测定时，表现出吸入麻醉药的敏感性，是最小的谷氨酸盐时，迅速施加在高浓度。由于这些是与突触传递最相关的条件，作者得出结论，AMPA受体不太可能在吸入剂产生麻醉状态中发挥主要作用。
BackgroundThere is substantial and growing literature on the actions of general anesthetics on a variety of neurotransmitter-gated ion channels, with the greatest attention being focused on inhibitory &ggr;-amino butyric acid type A receptors. In contrast, glutamate receptors, the most important class of fast excitatory neurotransmitter-gated receptor channels, have received much less attention, and their role in the production of the anesthetic state remains controversial. Methods&agr;-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors formed from a variety of different subunits were expressed in Xenopus oocytes and HEK-293 cells, and their sensitivities to the inhalational general anesthetics xenon, isoflurane, and halothane were determined using two-electrode voltage clamp and patch clamp techniques. The effects of desensitization on anesthetic sensitivity were investigated using cyclothiazide and site-directed mutagenesis. An ultrarapid application system was also used to mimic rapid high-concentration glutamate release at synapses. ResultsThe authors show that xenon can potently inhibit AMPA receptors when assayed using bath application of kainate. However, when the natural neurotransmitter l-glutamate is used under conditions in which the receptor desensitization is blocked and the peak of the glutamate-activated response can be accurately measured, the pattern of inhibition changes markedly. When desensitization is abolished by a single-point mutation (L497Y in GluR1 and the equivalent mutation L505Y in GluR4), the xenon inhibition is eliminated. When AMPA receptors are activated by glutamate using an ultrarapid application system that mimics synaptic conditions, sensitivity to xenon, halothane, and isoflurane is negligible. ConclusionsAMPA receptors, when assayed in heterologous expression systems, showed a sensitivity to inhalational anesthetics that was minimal when glutamate was applied rapidly at high concentrations. Because these are the conditions that are most relevant to synaptic transmission, the authors conclude that AMPA receptors are unlikely to play a major role in the production of the anesthetic state by inhalational agents.
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影响因子：
56.9
作者：
Rosenmund, C;Stern-Bach, Y;Stevens, CF
通讯作者：
Stevens, CF
AMPA 受体竞争性拮抗作用可降低大鼠中的氟烷 MAC。
影响因子：
8.8
作者：
McFarlane,C;Warner,DS;Todd,MM;Nordholm,L
通讯作者：
Nordholm,L
DOI：
--
发表时间：
1996-03
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
J. E. Dildy-Mayfield;Edmond I. Eger;R. Harris
通讯作者：
J. E. Dildy-Mayfield;Edmond I. Eger;R. Harris
挥发性麻醉剂对大鼠海马突触传递的影响。
影响因子：
8.8
作者：
Pearce,RA;Stringer,JL;Lothman,EW
通讯作者：
Lothman,EW