挥发性麻醉剂对M3毒蕈碱受体与Gαq异源三聚体G蛋白偶联的不同影响。

Differential effects of volatile anesthetics on M3 muscarinic receptor coupling to the Galphaq heterotrimeric G protein.

作者信息

Nakayama Tetsuzo, Penheiter Alan R, Penheiter Sumedha G, Chini Eduardo N, Thompson Michael, Warner David O, Jones Keith A

机构信息

Department of Anesthesiology, Mayo Foundation, Rochester, Minnesota 55905, USA.

出版信息

Anesthesiology. 2006 Aug;105(2):313-24. doi: 10.1097/00000542-200608000-00014.

DOI:10.1097/00000542-200608000-00014

PMID:16871065

Abstract

BACKGROUND

Halothane inhibits airway smooth muscle contraction in part by inhibiting the functional coupling between muscarinic receptors and one of its cognate heterotrimeric G proteins, Galphaq. Based on previous studies indicating a more potent effect of halothane and sevoflurane on airway smooth muscle contraction compared with isoflurane, the current study hypothesized that at anesthetic concentrations of 2 minimum alveolar concentration (MAC) or less, halothane and sevoflurane but not isoflurane inhibit acetylcholine-promoted Galphaq guanosine nucleotide exchange.

METHODS

Galphaq guanosine nucleotide exchange was measured in crude membranes prepared from COS-7 cells transiently coexpressing the human M3 muscarinic receptor and human Galphaq. A radioactive, nonhydrolyzable analog of guanosine-5'-triphosphate, [35S]GTPgammaS, was used as a reporter for nucleotide exchange at Galphaq.

RESULTS

Acetylcholine caused a concentration-dependent increase in Galphaq [35S]GTPgammaS-GDP exchange. Neither anesthetic affected constitutive Galphaq [35S]GTPgammaS-GDP exchange in the absence of acetylcholine. Conversely, each anesthetic caused a concentration-dependent and reversible inhibition of Galphaq [35S]GTPgammaS-GDP exchange when promoted by acetylcholine. At concentrations of 3 MAC or less, the effect of halothane and sevoflurane were significantly greater than that of isoflurane, with only a minimal inhibition by isoflurane observed at 2 MAC.

CONCLUSION

The differential effects of volatile anesthetics on acetylcholine-promoted guanosine nucleotide exchange at Galphaq are consistent with the apparent more potent direct effect of halothane and sevoflurane compared with isoflurane on muscarinic receptor-mediated contraction of isolated airway smooth muscle. These differential effects also suggest a mode of anesthetic action that could be due to anesthetic-protein interactions and not simply anesthetic accumulation in the lipid membrane.

摘要

背景

氟烷部分通过抑制毒蕈碱受体与其同源异三聚体G蛋白之一Gαq之间的功能偶联来抑制气道平滑肌收缩。基于先前的研究表明，与异氟烷相比，氟烷和七氟烷对气道平滑肌收缩的作用更强，当前研究假设在2个最低肺泡浓度（MAC）或更低的麻醉浓度下，氟烷和七氟烷而非异氟烷会抑制乙酰胆碱促进的Gαq鸟苷核苷酸交换。

方法

在瞬时共表达人M3毒蕈碱受体和人Gαq的COS-7细胞制备的粗制膜中测量Gαq鸟苷核苷酸交换。使用放射性、不可水解的鸟苷-5'-三磷酸类似物[35S]GTPγS作为Gαq核苷酸交换的报告分子。

结果

乙酰胆碱导致Gαq[35S]GTPγS-GDP交换呈浓度依赖性增加。在没有乙酰胆碱的情况下，两种麻醉剂均未影响组成型Gαq[35S]GTPγS-GDP交换。相反，当由乙酰胆碱促进时，每种麻醉剂均导致Gαq[35S]GTPγS-GDP交换呈浓度依赖性和可逆性抑制。在3 MAC或更低的浓度下，氟烷和七氟烷的作用明显大于异氟烷，在2 MAC时仅观察到异氟烷的最小抑制作用。