title: Dexmedetomidine inhibits muscarinic type 3 receptors expressed in Xenopus oocytes and muscarine-induced intracellular Ca2+ elevation in cultured rat dorsal root ganglia cells.
abstract: Dexmedetomidine, an alpha(2)-adrenoceptor agonist, has been approved for clinical use, although the mechanism of dexmedetomidine action has not been fully elucidated. Several studies have shown that G protein-coupled receptors (GPCRs) are recognized as targets for anesthetics and analgesics. Therefore, it is of interest to determine whether dexmedetomidine affects the function of GPCRs other than the alpha(2)-adrenoceptor. We examined the effects of dexmedetomidine on M(1), M(3), 5-HT(2C), substance P, and orexin 1 receptors in Xenopus oocytes expressing individual receptors. In addition, we investigated the effects of dexmedetomidine on muscarinic receptor-mediated changes in [Ca(2+)](i) in the dorsal root ganglia (DRG) of 3-week-old Wister rats. Dexmedetomidine did not affect the 5-HT(2C)-, or substance P-induced Cl(-) currents and had little inhibition on the orexin A-induced current in oocytes expressing the respective receptors. The compound also had little effect on the acetylcholine (ACh, 1 microM)-induced Ca(2+)-activated Cl(-) currents in Xenopus oocytes expressing M(1) receptors. In contrast, dexmedetomidine inhibited the ACh-induced currents in Xenopus oocytes expressing M(3) receptors; 1 nM, 10 nM, 100 nM, and 1 microM dexmedetomidine reduced the current to 66.5 +/- 4.8, 51.3 +/- 12, 34.6 +/- 11, and 26.8 +/- 6.4% of the control value, respectively (EC(50) = 3.5 +/- 0.7 nM). Dexmedetomidine reduced the ACh-induced Cl(-) currents after treatment with the selective protein kinase C inhibitor GF109203X. Moreover, the compound inhibited the muscarinic receptor-mediated increases in [Ca(2+)](i) in cultured DRG cells in a concentration-dependent manner. Dexmedetomidine inhibits the function of M(3) receptors, in addition to its agonistic effects on alpha(2)-adrenoceptors, which provides further insight into the pharmacological properties of dexmedetomidine.
authors.affiliation: Department of Anesthesiology, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishiku, Kitakyushu, 807-8555, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takizuka
authors.forename: Kouichiro
authors.initials: K
authors.lastname: Minami
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Uezono
authors.forename: Takafumi
authors.initials: T
authors.lastname: Horishita
authors.forename: Toru
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Munehiro
authors.initials: M
authors.lastname: Shiraishi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Akio
authors.initials: A
authors.lastname: Shigematsu
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Ueta
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D018118:Chloride Channels / Q000502:physiology; D020927:Dexmedetomidine / Q000494:pharmacology*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D007424:Intracellular Fluid / Q000378:metabolism; D009116:Muscarine / Q000494:pharmacology; D009865:Oocytes / Q000378:metabolism; D064446:Orexin Receptors; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000187:drug effects / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000187:drug effects / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D000316:Adrenergic alpha-Agonists; D018712:Analgesics, Non-Narcotic; D018118:Chloride Channels; D006993:Hypnotics and Sedatives; D064446:Orexin Receptors; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D044405:Receptor, Serotonin, 5-HT2C; D043562:Receptors, G-Protein-Coupled; D018040:Receptors, Neurokinin-1; D018013:Receptors, Neuropeptide; D020927:Dexmedetomidine; D009116:Muscarine; D000109:Acetylcholine; D002118:Calcium