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Propofol Anesthesia Is Reduced in Phospholipase C-Related Inactive Protein Type-1 Knockout Mice
Yoshikazu Nikaido1, Tomonori Furukawa1, Shuji Shimoyama1
1Graduate School of Medicine (Y.N.), Department of Neurophysiology (Y.N., T.F., K.K., S.U.) and Department of Anesthesiology, Graduate School of Medicine (Y.N., T.Ku., K.H.), Research Center for Child Mental Development, Graduate School of Medicine (S.S., S.U.), and Department of Biomedical Sciences, Division of Medical Life Sciences, Graduate School of Health Sciences (J.Y.), Hirosaki University, Hirosaki, Japan; Department of Drug Informatics, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan (K.M.); Department of Cellular and Molecular Pharmacology, Division of Basic Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan (T.Ka.); Laboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu University, Fukuoka, Japan (M.H.); Fukuoka Dental College, Fukuoka, Japan (M.H.).
Abstract:
The GABA type A receptor (GABAA-R) is a major target of intravenous anesthetics. Phospholipase C-related inactive protein type-1 (PRIP-1) is important in GABAA-R phosphorylation and membrane trafficking. In this study, we investigated the role of PRIP-1 in general anesthetic action. The anesthetic effects of propofol, etomidate, and pentobarbital were evaluated in wild-type and PRIP-1 knockout (PRIP-1 KO) mice by measuring the latency and duration of loss of righting reflex (LORR) and loss of tail-pinch withdrawal response (LTWR). The effect of pretreatment with okadaic acid (OA), a protein phosphatase 1/2A inhibitor, on propofol- and etomidate-induced LORR was also examined. PRIP-1 deficiency provided the reduction of LORR and LTWR induced by propofol but not by etomidate or pentobarbital, indicating that PRIP-1 could determine the potency of the anesthetic action of propofol. Pretreatment with OA recovered the anesthetic potency induced by propofol in PRIP-1 KO mice. OA injection enhanced phosphorylation of cortical the GABAA-R β3 subunit in PRIP-1 KO mice. These results suggest that PRIP-1-mediated GABAA-R β3 subunit phosphorylation might be involved in the general anesthetic action induced by propofol but not by etomidate or pentobarbital.