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NEUROPHARMACOLOGY

Site of Action of the General Anesthetic Propofol in Muscarinic M1 Receptor-Mediated Signal Transduction

Departments of Pharmacology (O.M., M.K., S.M., Y.D., K.T.) and Anesthesiology (Y.N., K.S.), Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

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 subunits (Gq). Propofol inhibited M1 receptor-mediated signal transduction in a dose-dependent manner (IC₅₀ = 50 nM). Injection of guanosine 5'-3-O-(thio)triphosphate (GTPS) into oocytes overexpressing Gq was used to investigate direct effects of propofol on G protein coupled with the M1 receptor. Propofol did not affect activation of Gq-mediated signal transduction with the intracellular injection of GTPS. 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 2 adrenoceptor (2 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 2 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.

Address correspondence to: Dr. Muneshige Kaibara, Department of Pharmacology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. E-mail: mkaibara{at}alpha.med.nagasaki-u.ac.jp