解离麻醉剂氯胺酮和地佐环平对人神经元烟碱型乙酰胆碱受体及其他配体门控离子通道的亚基依赖性抑制作用。

Subunit-dependent inhibition of human neuronal nicotinic acetylcholine receptors and other ligand-gated ion channels by dissociative anesthetics ketamine and dizocilpine.

作者信息

Yamakura T, Chavez-Noriega L E, Harris R A

机构信息

Institute for Cellular and Molecular Biology, University of Texas, Austin 78712-1095, USA.

出版信息

Anesthesiology. 2000 Apr;92(4):1144-53. doi: 10.1097/00000542-200004000-00033.

DOI:10.1097/00000542-200004000-00033

PMID:10754635

Abstract

UNLABELLED

Background The neuronal mechanisms responsible for dissociative anesthesia remain controversial. N-methyl-D-aspartate (NMDA) receptors are inhibited by ketamine and related drugs at concentrations lower than those required for anesthetic effects. Thus, the authors studied whether ligand-gated ion channels other than NMDA receptors might display a sensitivity to ketamine and dizocilpine that is consistent with concentrations required for anesthesia.

METHODS

Heteromeric human neuronal nicotinic acetylcholine receptors (hnAChR channels alpha2beta2, alpha2beta4, alpha3beta2, alpha3beta4, alpha4beta2 and alpha4beta4), 5-hydroxytryptamine3 (5-HT3), alpha1beta2gamma2S gamma-aminobutyric acid type A (GABAA) and alpha1 glycine receptors were expressed in Xenopus oocytes, and effects of ketamine and dizocilpine were studied using the two-electrode voltage-clamp technique.

RESULTS

Both ketamine and dizocilpine inhibited hnAChRs in a noncompetitive and voltage-dependent manner. Receptors containing beta1 subunits were more sensitive to ketamine and dizocilpine than those containing beta2 subunits. The inhibitor concentration for half-maximal response (IC50) values for ketamine of hnAChRs composed of beta4 subunits were 9.5-29 microM, whereas those of beta2 subunits were 50-92 microM. Conversely, 5-HT3 receptors were inhibited only by concentrations of ketamine and dizocilpine higher than the anesthetic concentrations. This inhibition was mixed (competitive/noncompetitive). GABAA and glycine receptors were very resistant to dissociative anesthetics.

CONCLUSIONS

Human nAChRs are inhibited by ketamine and dizocilpine at concentrations possibly achieved in vivo during anesthesia in a subunit-dependent manner, with beta subunits being more critical than alpha subunits. Conversely, 5-HT3, GABAA, and glycine receptors were relatively insensitive to dissociative anesthetics.

摘要

未标注

背景负责分离麻醉的神经元机制仍存在争议。氯胺酮及相关药物在低于产生麻醉效果所需浓度时就能抑制N-甲基-D-天冬氨酸（NMDA）受体。因此，作者研究了除NMDA受体之外的配体门控离子通道是否可能对氯胺酮和地佐环平表现出与麻醉所需浓度一致的敏感性。

方法

将异源三聚体人神经元烟碱型乙酰胆碱受体（hnAChR通道α2β2、α2β4、α3β2、α3β4、α4β2和α4β4）、5-羟色胺3（5-HT3）、α1β2γ2S γ-氨基丁酸A型（GABAA）和α1甘氨酸受体在非洲爪蟾卵母细胞中表达，并使用双电极电压钳技术研究氯胺酮和地佐环平的作用。

结果

氯胺酮和地佐环平均以非竞争性和电压依赖性方式抑制hnAChRs。含有β1亚基的受体比含有β2亚基的受体对氯胺酮和地佐环平更敏感。由β4亚基组成的hnAChRs对氯胺酮的半数最大反应抑制浓度（IC₅₀）值为9.5 - 29微摩尔，而由β2亚基组成的则为50 - 92微摩尔。相反，5-HT3受体仅在高于麻醉浓度的氯胺酮和地佐环平浓度下才受到抑制。这种抑制是混合性的（竞争性/非竞争性）。GABAA和甘氨酸受体对分离麻醉药具有很强的抗性。