Antagonism of inhalant and volatile anesthetic enhancement of glycine receptor function
Antagonism of inhalant and volatile anesthetic enhancement of glycine receptor function
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DOI：
10.1074/jbc.m011627200
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发表时间：
2001-07-06
影响因子：
4.8
通讯作者：
Mihic, SJ
中科院分区：
文献类型：
--
作者：
Beckstead, MJ;Phelan, R;Mihic, SJ
最近的研究表明，增强γ-氨基丁酸、A型和甘氨酸受体激活的离子通道功能的酒精、挥发性麻醉剂和滥用的吸入药物可能对这些受体具有共同或重叠的分子作用位点。为了研究这种可能性，将这些化合物单独和组合应用于非洲爪蟾卵母细胞中表达的野生型甘氨酸cu受体，在存在和不存在乙醇、氯仿或甲苯的情况下，从挥发性麻醉剂安氟醚的浓度-反应曲线获得的数据与这些受体上共同结合口袋的竞争一致，突变甘氨酸受体，对乙醇的增强作用不敏感，但对麻醉剂或吸入剂不敏感，证明了麻醉剂和吸入剂对该受体的拮抗作用。虽然乙醇（25-200 mM）本身对该受体没有影响，但它能够以浓度依赖性方式可逆地抑制恩氟烷、甲苯和氯仿的增强作用。这些数据表明乙醇、吸入剂和挥发性麻醉剂对甘氨酸受体的作用存在重叠的分子位点，并说明了挥发性麻醉剂药理学拮抗作用的可行性。
Recent studies suggest that alcohols, volatile anesthetics, and inhaled drugs of abuse, which enhance gamma -aminobutyric acid, type A, and glycine receptor-activated ion channel function, may share common or overlapping molecular sites of action on these receptors, To investigate this possibility, these compounds were applied singly and in combination to wild-type glycine cu, receptors expressed in Xenopus laevis oocytes, Data obtained from concentration-response curves of the volatile anesthetic enflurane constructed in the presence and absence of ethanol, chloroform, or toluene were consistent with competition for a common binding pocket on these receptors, A mutant glycine receptor, insensitive to the enhancing effects of ethanol but not anesthetics or inhalants, demonstrated antagonism of anesthetic and inhalent effects on this receptor. Although ethanol (25-200 mM) had no effect on its own in this receptor, it was able to inhibit reversibly the enhancing effect of enflurane, toluene, and chloroform in a concentration-dependent manner. These data suggest the existence of overlapping molecular sites of action for ethanol, inhalants, and volatile anesthetics on glycine receptors and illustrate the feasibility of pharmacological antagonism of the effects of volatile anesthetics.