Department of Anesthesiology and Pain Medicine and Anesthesia and Pain Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea.
Neurosci Lett. 2009 Nov 13;465(2):147-50. doi: 10.1016/j.neulet.2009.09.021. Epub 2009 Sep 16.
5-Hydroxytryptamine type 3 (5-HT(3)) receptor is modulated by general anesthetics and regarded as a possible site of anesthetic adverse action. Although two amino acids located in transmembrane (TM) 2 and TM3 of LGICs were reported as critical for allosteric modulation by anesthetics and alcohols, other residues could regulate anesthetic modulation. Earlier studies identified the role of glutamate 129 and phenylalanine 130 in the non-TM extracellular region in the agonist binding and coupling in the 5-HT(3A) receptor. We investigated whether these non-TM amino acids are involved in desflurane and propofol modulation of the 5-HT(3A) receptor in mutant 5-HT(3A) receptors (mutants) expressed in Xenopus laevis oocytes. E129D and F130Y mutants were functionally expressed but E129Y and F130S mutants were not gated by serotonin. The wild type and F130Y mutants demonstrated positive modulation by desflurane at 6 and 12vol.%. In contrast, E129D mutants were inhibited by desflurane in a concentration dependent manner. Propofol (1-100 microM) demonstrated depression of the currents in all receptors examined. These findings suggest the role of non-TM residues in the extracellular domain in the anesthetic modulation of the 5-HT(3A) receptor.
5-羟色胺 3（5-HT（3））受体被全身麻醉剂调节，被认为是麻醉不良反应的可能部位。虽然位于 LGICs 的跨膜（TM）2 和 TM3 中的两个氨基酸被报道为麻醉剂和醇的变构调节的关键，但其他残基也可以调节麻醉剂的调节。早期的研究确定了非 TM 细胞外区域中谷氨酸 129 和苯丙氨酸 130 在 5-HT（3A）受体的激动剂结合和偶联中的作用。我们研究了这些非 TM 氨基酸是否参与了氟烷和异丙酚对在非洲爪蟾卵母细胞中表达的 5-HT（3A）受体的调制。E129D 和 F130Y 突变体可被功能表达，但 E129Y 和 F130S 突变体不能被 5-羟色胺门控。野生型和 F130Y 突变体对氟烷的 6 和 12vol。%表现出正调节。相比之下，E129D 突变体被氟烷以浓度依赖性方式抑制。丙泊酚（1-100μM）显示所有被检查的受体电流的抑制。这些发现表明非 TM 残基在细胞外结构域在 5-HT（3A）受体的麻醉调节中的作用。
