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General anesthetic actions on GABAA receptors in vivo are reduced in phospholipase C-related catalytically inactive protein knockout mice

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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.

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Acknowledgements

We thank the staff of the Natural Science Center for Basic Research and Development (NBARD) at Hiroshima University for assistance with mouse breeding. This work was supported in part by grants from the Japan Society for the Promotion of Science (JSPS; Kakenhi, Grant Numbers: JP26670809 and JP16K11503 to T. Kanematsu, JP15K11313 to M. I.).

Author information

Author notes

  1. Tomoya Kitayama

    Present address: Pharmaceutical Education Support Center, Mukogawa Women’s University, 6-46 Ikebiraki-cho, Nishinomiya, Hyogo, 663-8558, Japan

  2. Kae Harada

    Present address: Department of Oral and Maxillofacial Prosthodontics, Graduate School of Medical and Dental Science, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8544, Japan

Authors and Affiliations

  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

    Masaki Hayashiuchi, Tomoya Kitayama, Yosuke Yamawaki, Kana Oue, Satoshi Asano, Kae Harada & Takashi Kanematsu

  2. Department of Special Care Dentistry, Hiroshima University Hospital, Hiroshima, 734-8553, Japan

    Masaki Hayashiuchi & Mitsugi Okada

  3. Department of Pharmacology, Faculty of Nursing, Hiroshima Bunka Gakuen University, 2-10-3 Agaminami, Kure, Hiroshima, 737-0004, Japan

    Katsuya Morita

  4. Department of Dental Anesthesiology, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan

    Kana Oue, Taiga Yoshinaka & Masahiro Irifune

  5. Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, 1-8 Yamada-Oka, Suita, Osaka, 565-0871, Japan

    Youngnam Kang

  6. Department of Neurobiology and Physiology, School of Dentistry, Seoul National University, Seoul, 110-749, Republic of Korea

    Youngnam Kang

  7. Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Masato Hirata

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  1. Masaki Hayashiuchi
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  2. Tomoya Kitayama
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  6. Taiga Yoshinaka
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  13. Takashi Kanematsu
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Corresponding author

Correspondence to Takashi Kanematsu.

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Hayashiuchi, M., Kitayama, T., Morita, K. et al. General anesthetic actions on GABAA receptors in vivo are reduced in phospholipase C-related catalytically inactive protein knockout mice. J Anesth 31, 531–538 (2017). https://doi.org/10.1007/s00540-017-2350-2

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  • DOI: https://doi.org/10.1007/s00540-017-2350-2

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