Minami K, Minami M, Harris R A
Department of Pharmacology, University of Colorado Health Sciences Center and Veterans Affairs Medical Center, Denver 80262, USA.
J Pharmacol Exp Ther. 1997 Jun;281(3):1136-43.
5-Hydroxytryptamine type 2A receptors (5-HT2A) are G protein-coupled receptors that increase intracellular Ca2+ concentrations via activation of phospholipase C-beta and elevation of myo-inositol-1,4,5-triphosphate levels. In the central nervous system, these receptors are involved in regulating sleep and alertness. We now report that ethanol inhibited (IC50 = 41 mM) 5-HT2A receptor-induced Ca2+-dependent Cl- currents in Xenopus laevis oocytes. Pharmacologically relevant concentrations of other n-alcohols (propanol to octanol) also inhibited 5-HT responses; however, longer-chain alcohols (decanol, undecanol and dodecanol) had little or no effect. The protein kinase C inhibitor GF109203X and the nonspecific protein kinase inhibitor staurosporine abolished the inhibitory effects of ethanol and octanol on 5-HT2A receptors. GF109203X enhanced 5-HT2A receptor function when administered alone. In addition, the volatile anesthetics halothane and 1-chloro-1,2,2-trifluorocyclobutane decreased 5-HT2A responses in a concentration-dependent manner. The inhibitory effects of the volatile anesthetics were also attenuated in oocytes treated with GF109203X. The intravenous anesthetics propofol, ketamine, pentobarbital and etomidate did not affect 5-HT2A receptor function. The modulation of 5-HT2A receptor-dependent current was also investigated using two novel halogenated compounds that do not produce anesthesia. The nonanesthetic compound 2,3-chloro-octafluorobutane had no effects on 5-HT-induced currents; however, the nonanesthetic compound 1,2-dichlorohexafluorocyclobutane had an inhibitory effect at lower concentrations than the predicted anesthetic concentration. Thus, 5-HT2A receptors are inhibited by alcohols and volatile anesthetics, and these actions are dependent on protein kinase C.
5-羟色胺2A型受体（5-HT2A）是G蛋白偶联受体，通过激活磷脂酶C-β和提高肌醇-1,4,5-三磷酸水平来增加细胞内Ca2+浓度。在中枢神经系统中，这些受体参与调节睡眠和警觉性。我们现在报告，乙醇在非洲爪蟾卵母细胞中抑制（IC50 = 41 mM）5-HT2A受体诱导的Ca2+依赖性Cl-电流。其他正醇（丙醇至辛醇）的药理学相关浓度也抑制5-HT反应；然而，长链醇（癸醇、十一烷醇和十二烷醇）几乎没有影响或没有影响。蛋白激酶C抑制剂GF109203X和非特异性蛋白激酶抑制剂星形孢菌素消除了乙醇和辛醇对5-HT2A受体的抑制作用。单独给药时，GF109203X增强了5-HT2A受体功能。此外，挥发性麻醉剂氟烷和1-氯-1,2,2-三氟环丁烷以浓度依赖性方式降低5-HT2A反应。在用GF109203X处理的卵母细胞中，挥发性麻醉剂的抑制作用也减弱。静脉麻醉剂丙泊酚、氯胺酮、戊巴比妥和依托咪酯不影响5-HT2A受体功能。还使用两种不产生麻醉作用的新型卤代化合物研究了对5-HT2A受体依赖性电流的调节。非麻醉化合物2,3-氯-八氟丁烷对5-HT诱导的电流没有影响；然而，非麻醉化合物1,2-二氯六氟环丁烷在低于预测麻醉浓度时具有抑制作用。因此，5-HT2A受体受到醇类和挥发性麻醉剂的抑制，并且这些作用依赖于蛋白激酶C。
