title: General anesthetic actions on GABAAreceptors in vivo are reduced in phospholipase C-related catalytically inactive protein knockout mice.
abstract: OBJECTIVE
  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 GABAAreceptor signaling.
  
  
  METHODS
  PRIP regulates the intracellular trafficking of β subunit-containing GABAAreceptors in vitro. In this study, we examined the effects of intravenous anesthetics, propofol and etomidate that act via β subunit-containing GABAAreceptors, 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 GABAAreceptor β3 subunit detected by immunoblotting was decreased in Prip-knockout brain compared with that in wild-type brain without changing the expression of other GABAAreceptor 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.
  
  
  CONCLUSIONS
  PRIP regulates the cell surface expression of the GABAAreceptor β3 subunit and modulates general anesthetic action in vivo. Elucidation of the involved regulatory mechanisms of GABAAreceptor-dependent signaling would inform the development of safer anesthetic therapies for clinical applications.
authors.affiliation: Department of Cellular and Molecular Pharmacology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.|Department of Special Care Dentistry, Hiroshima University Hospital, Hiroshima, 734-8553, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Hayashiuchi
authors.affiliation: Department of Cellular and Molecular Pharmacology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.|Pharmaceutical Education Support Center, Mukogawa Women's University, 6-46 Ikebiraki-cho, Nishinomiya, Hyogo, 663-8558, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kitayama
authors.affiliation: Department of Pharmacology, Faculty of Nursing, Hiroshima Bunka Gakuen University, 2-10-3 Agaminami, Kure, Hiroshima, 737-0004, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Morita
authors.affiliation: Department of Cellular and Molecular Pharmacology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Yamawaki
authors.affiliation: Department of Cellular and Molecular Pharmacology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.|Department of Dental Anesthesiology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Oue
authors.affiliation: Department of Dental Anesthesiology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Taiga
authors.initials: T
authors.lastname: Yoshinaka
authors.affiliation: Department of Cellular and Molecular Pharmacology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Asano
authors.affiliation: Department of Cellular and Molecular Pharmacology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.|Department of Oral and Maxillofacial Prosthodontics, Graduate School of Medical and Dental Science, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan.
authors.forename: Kae
authors.initials: K
authors.lastname: Harada
authors.affiliation: Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, 1-8 Yamada-Oka, Suita, Osaka, 565-0871, Japan.|Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, 110-749, Republic of Korea.
authors.forename: Youngnam
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Department of Dental Anesthesiology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Irifune
authors.affiliation: Department of Special Care Dentistry, Hiroshima University Hospital, Hiroshima, 734-8553, Japan.
authors.forename: Mitsugi
authors.initials: M
authors.lastname: Okada
authors.affiliation: 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.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kanematsu
mesh_terms: D000768:Anesthesia, General; D018681:Anesthetics, General / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000008:administration & dosage; D000818:Animals; D004569:Electroencephalography; D005045:Etomidate / Q000008:administration & dosage; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D056918:Nuclear Receptor Coactivators / Q000235:genetics*; D015742:Propofol / Q000008:administration & dosage; D011963:Receptors, GABA-A / Q000187:drug effects*
chemical_list: D018681:Anesthetics, General; D018686:Anesthetics, Intravenous; D006993:Hypnotics and Sedatives; C405683:Ncoa6 protein, mouse; D056918:Nuclear Receptor Coactivators; D011963:Receptors, GABA-A; D015742:Propofol; D005045:Etomidate
keywords: Etomidate; GABAA receptor; GABAA receptor β3 subunit; Propofol; Righting reflex