Masaki Hayashiuchi1,2, Tomoya Kitayama1,3, Katsuya Morita4, Yosuke Yamawaki1, Kana Oue1,5, Taiga Yoshinaka5, Satoshi Asano1, Kae Harada1,6, Youngnam Kang7,8, Masato Hirata9, Masahiro Irifune5, Mitsugi Okada2, Takashi Kanematsu10. 1. Department of Cellular and Molecular Pharmacology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan. 2. Department of Special Care Dentistry, Hiroshima University Hospital, Hiroshima, 734-8553, Japan. 3. Pharmaceutical Education Support Center, Mukogawa Women's University, 6-46 Ikebiraki-cho, Nishinomiya, Hyogo, 663-8558, Japan. 4. Department of Pharmacology, Faculty of Nursing, Hiroshima Bunka Gakuen University, 2-10-3 Agaminami, Kure, Hiroshima, 737-0004, Japan. 5. Department of Dental Anesthesiology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan. 6. Department of Oral and Maxillofacial Prosthodontics, Graduate School of Medical and Dental Science, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan. 7. Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, 1-8 Yamada-Oka, Suita, Osaka, 565-0871, Japan. 8. Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, 110-749, Republic of Korea. 9. Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. 10. Department of Cellular and Molecular Pharmacology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan. tkanema2@hiroshima-u.ac.jp.
Abstract
PURPOSE: The aim of this study was to investigate the action of general anesthetics in phospholipase C-related catalytically inactive protein (PRIP)-knockout (KO) mice that alter GABAA receptor signaling. METHODS: PRIP regulates the intracellular trafficking of β subunit-containing GABAA receptors in vitro. In this study, we examined the effects of intravenous anesthetics, propofol and etomidate that act via β subunit-containing GABAA receptors, in wild-type and Prip-KO mice. Mice were intraperitoneally injected with a drug, and a loss of righting reflex (LORR) assay and an electroencephalogram analysis were performed. RESULTS: The cell surface expression of GABAA receptor β3 subunit detected by immunoblotting was decreased in Prip-knockout brain compared with that in wild-type brain without changing the expression of other GABAA receptor subunits. Propofol-treated Prip-KO mice exhibited significantly shorter duration of LORR and had lower total anesthetic score than wild-type mice in the LORR assay. The average duration of sleep time in an electroencephalogram analysis was shorter in propofol-treated Prip-KO mice than in wild-type mice. The hypnotic action of etomidate was also reduced in Prip-KO mice. However, ketamine, an NMDA receptor antagonist, had similar effects in the two genotypes. CONCLUSION: PRIP regulates the cell surface expression of the GABAA receptor β3 subunit and modulates general anesthetic action in vivo. Elucidation of the involved regulatory mechanisms of GABAA receptor-dependent signaling would inform the development of safer anesthetic therapies for clinical applications.
PURPOSE: The aim of this study was to investigate the action of general anesthetics in phospholipase C-related catalytically inactive protein (PRIP)-knockout (KO) mice that alter GABAA receptor signaling. METHODS:PRIP regulates the intracellular trafficking of β subunit-containing GABAA receptors in vitro. In this study, we examined the effects of intravenous anesthetics, propofol and etomidate that act via β subunit-containing GABAA receptors, in wild-type and Prip-KO mice. Mice were intraperitoneally injected with a drug, and a loss of righting reflex (LORR) assay and an electroencephalogram analysis were performed. RESULTS: The cell surface expression of GABAA receptor β3 subunit detected by immunoblotting was decreased in Prip-knockout brain compared with that in wild-type brain without changing the expression of other GABAA receptor subunits. Propofol-treated Prip-KO mice exhibited significantly shorter duration of LORR and had lower total anesthetic score than wild-type mice in the LORR assay. The average duration of sleep time in an electroencephalogram analysis was shorter in propofol-treated Prip-KO mice than in wild-type mice. The hypnotic action of etomidate was also reduced in Prip-KO mice. However, ketamine, an NMDA receptor antagonist, had similar effects in the two genotypes. CONCLUSION:PRIP regulates the cell surface expression of the GABAA receptor β3 subunit and modulates general anesthetic action in vivo. Elucidation of the involved regulatory mechanisms of GABAA receptor-dependent signaling would inform the development of safer anesthetic therapies for clinical applications.
Authors: Simon P Fisher; Sarah W Black; Michael D Schwartz; Alan J Wilk; Tsui-Ming Chen; Webster U Lincoln; Helen W Liu; Thomas S Kilduff; Stephen R Morairty Journal: Brain Date: 2013-07 Impact factor: 13.501
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Authors: David S Reynolds; Thomas W Rosahl; Jennifer Cirone; Gillian F O'Meara; Alison Haythornthwaite; Richard J Newman; Janice Myers; Cyrille Sur; Owain Howell; A Richard Rutter; John Atack; Alison J Macaulay; Karen L Hadingham; Peter H Hutson; Delia Belelli; Jeremy J Lambert; Gerard R Dawson; Ruth McKernan; Paul J Whiting; Keith A Wafford Journal: J Neurosci Date: 2003-09-17 Impact factor: 6.167