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.
Footnotes
- Received November 30, 2016.
- Accepted April 4, 2017.
This work was supported by a Hirosaki University Institutional Research grant; a Karoji Memorial Fund for Medical Research grant; the Japan Society for the Promotion of Science KAKENHI [Grants 23659735, 24229009, 25670663]; and the Ministry of Education, Culture, Sports, Science and Technology KAKENHI [Grants 23592242, 24659690].
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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