TY - JOUR T1 - Site of Action of the General Anesthetic Propofol in Muscarinic M1 Receptor-Mediated Signal Transduction JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 995 LP - 1000 DO - 10.1124/jpet.103.055772 VL - 307 IS - 3 AU - Osamu Murasaki AU - Muneshige Kaibara AU - Yoshihisa Nagase AU - Sayaka Mitarai AU - Yoshiyuki Doi AU - Koji Sumikawa AU - Kohtaro Taniyama Y1 - 2003/12/01 UR - http://jpet.aspetjournals.org/content/307/3/995.abstract N2 - Although a potential target site of general anesthetics is primarily the GABA A receptor, a chloride ion channel, a previous study suggested that the intravenous general anesthetic propofol attenuates the M1 muscarinic acetylcholine receptor (M1 receptor)-mediated signal transduction. In the present study, we examined the target site of propofol in M1 receptor-mediated signal transduction. Two-electrode voltage-clamp method was used in Xenopus oocytes expressing both M1 receptors and associated G protein α subunits (Gqα). Propofol inhibited M1 receptor-mediated signal transduction in a dose-dependent manner (IC50 = 50 nM). Injection of guanosine 5′-3-O-(thio)triphosphate (GTPγS) into oocytes overexpressing Gqα was used to investigate direct effects of propofol on G protein coupled with the M1 receptor. Propofol did not affect activation of Gqα-mediated signal transduction with the intracellular injection of GTPγS. We also studied effects of propofol on l-[N-methyl-3H]scopolamine methyl chloride ([3H]NMS) binding and M1 receptor-mediated signal transduction in mammalian cells expressing M1 receptor. Propofol inhibited the M1 receptor-mediated signal transduction but did not inhibit binding of [3H]NMS. Effects of propofol on Gs- and Gi/o-coupled signal transduction were investigated, using oocytes expressing the β2 adrenoceptor (β2 receptor)/cystic fibrosis transmembrane conductance regulator or oocytes expressing the M2 muscarinic acetylcholine receptor (M2 receptor)/Kir3.1 (a member of G protein-gated inwardly rectifying K+ channels). Neither β2 receptor-mediated nor M2 receptor-mediated signal transduction was inhibited by a relatively high concentration of propofol (50 μM). These results indicate that propofol inhibits M1 receptor-mediated signal transduction by selectively disrupting interaction between the receptor and associated G protein. The American Society for Pharmacology and Experimental Therapeutics ER -