Lees G, Edwards M D
Academic Department of Anesthetics, Imperial College of Science, Technology and Medicine at St. Mary's Hospital Medical School, London, United Kingdom.
Anesthesiology. 1998 Jan;88(1):206-17. doi: 10.1097/00000542-199801000-00029.
The gamma-aminobutyric acid (GABA)A receptor/chloride channel has a broad-spectrum anesthetic sensitivity and is a key regulator of arousal. Each receptor/channel complex is an assembly of five protein subunits. Six subunit classes have been identified, each containing one to six members; many combinations are expressed throughout the brain. Benzodiazepines and intravenous anesthetic agents are clearly subunit dependent, but the literature to date suggests that volatile anesthetics are not. The physiological role of the delta subunit remains enigmatic, and it has not been examined as a determinant of anesthetic sensitivity.
Combinations of GABA(A) receptor subunit cDNAs were injected into Xenopus laevis oocytes: alpha1beta1, alpha1beta1gamma2L, alpha1beta1delta, and alpha1beta1gamma2Ldelta. Expression of functional ion channels with distinct signalling and pharmacologic properties was demonstrated within 1-4 days by established electrophysiological methods.
Co-expression of the delta subunit produced changes in receptor affinity; current density; and the modulatory efficacy of diazepam, zinc, and lanthanum; it also produced subtle changes in the rate of desensitization in response to GABA. Isoflurane enhanced GABA-induced responses from all combinations: alphabeta delta (>10-fold) > alphabeta > alphabeta gamma > or = alphabeta gammadelta (approximately 5-fold). Dose-response plots were bell shaped. Compared with alphabeta gamma receptors (EC50 = 225 microM), both alphabeta delta (EC50 = 372 microM) and alphabeta gammadelta (EC50 = 399 microM) had a reduced affinity for isoflurane. Isoflurane (at a concentration close to the EC50 for each subunit) increased the affinity of GABA for its receptor but depressed the maximal response (alphabeta gamma and alphabeta gammadelta). In contrast, the small currents through alphabeta delta receptors were enhanced, even at saturating agonist concentrations.
Delta subunit expression alters GABA(A) receptor function but is not an absolute determinant of anesthetic sensitivity.
γ-氨基丁酸（GABA）A受体/氯离子通道具有广谱麻醉敏感性，是觉醒的关键调节因子。每个受体/通道复合物由五个蛋白质亚基组装而成。已鉴定出六种亚基类型，每种包含一至六个成员；许多组合在整个大脑中表达。苯二氮䓬类药物和静脉麻醉剂显然依赖于亚基，但迄今为止的文献表明挥发性麻醉剂并非如此。δ亚基的生理作用仍然不明，尚未作为麻醉敏感性的决定因素进行研究。
将GABA（A）受体亚基cDNA的组合注射到非洲爪蟾卵母细胞中：α1β1、α1β1γ2L、α1β1δ和α1β1γ2Lδ。通过既定的电生理方法在1 - 4天内证明了具有不同信号和药理特性的功能性离子通道的表达。
δ亚基的共表达导致受体亲和力、电流密度以及地西泮、锌和镧的调节效能发生变化；它还使对GABA脱敏速率产生细微变化。异氟烷增强了所有组合的GABA诱导反应：αβδ（>10倍）>αβ>αβγ≥αβγδ（约5倍）。剂量反应曲线呈钟形。与αβγ受体（EC50 = 225微摩尔）相比，αβδ（EC50 = 372微摩尔）和αβγδ（EC50 = 399微摩尔）对异氟烷的亲和力均降低。异氟烷（在接近每个亚基EC50的浓度下）增加了GABA与其受体的亲和力，但降低了最大反应（αβγ和αβγδ）。相比之下，即使在激动剂饱和浓度下，通过αβδ受体的小电流也增强了。
δ亚基表达改变GABA（A）受体功能，但不是麻醉敏感性的绝对决定因素。
