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

• Published in: The Journal of pharmacology and experimental therapeutics 2003-12, Vol.307 (3), p.995-1000
• Main Authors: Murasaki, Osamu, Kaibara, Muneshige, Nagase, Yoshihisa, Mitarai, Sayaka, Doi, Yoshiyuki, Sumikawa, Koji, Taniyama, Kohtaro
• Format: Article
• Language: English
• Subjects: Acetylcholine - metabolism; Anesthetics, Intravenous - pharmacology; Animals; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; DNA, Complementary - biosynthesis; DNA, Complementary - genetics; Electrophysiology; G Protein-Coupled Inwardly-Rectifying Potassium Channels; GTP-Binding Protein alpha Subunits, Gi-Go - physiology; GTP-Binding Protein alpha Subunits, Gs - physiology; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; N-Methylscopolamine - metabolism; Oocytes - metabolism; Parasympatholytics - metabolism; Patch-Clamp Techniques; Potassium Channels - drug effects; Potassium Channels - metabolism; Potassium Channels, Inwardly Rectifying; Propofol - pharmacology; Radioligand Assay; Rats; Receptor, Muscarinic M1 - drug effects; Receptor, Muscarinic M1 - metabolism; Receptor, Muscarinic M2 - drug effects; Receptor, Muscarinic M2 - metabolism; Signal Transduction - drug effects; Xenopus laevis
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.055772

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 (IC 50 = 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- 3 H]scopolamine methyl chloride ([ 3 H]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 [ 3 H]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.