Sevoflurane alters α5β3GABAA receptor trafficking via calcium/calmodulin-dependent protein kinase II-dependent β3 subunit phosphorylation to produce cognitive impairment in aged mice

  • Br J Anaesth. 2026 Jan 27:S0007-0912(25)00893-1. doi: 10.1016/j.bja.2025.11.058.
Tiantian Wan  1 ,  Mengxue Zhang  2 ,  Jianjun Li  3 ,  Zhun Wang  2 ,  Jinpeng Dong  2 ,  Xiaokun Wang  2 ,  Zhonglan Dong  2 ,  Qiangwei Liu  2 ,  Ying Dong  2 ,  Sixuan Wang  2 ,  Lu Chen  2 ,  Yiqing Yin  4
Affiliations
  • 1. Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China; Department of Anesthesiology, the First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China.
  • 2. Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China.
  • 3. Department of Anesthesiology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao, China.
  • 4. Department of Anesthesiology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China; Key Laboratory of Cancer Prevention and Therapy, Tianjin, China; Tianjin's Clinical Research Center for Cancer, Tianjin, China. Electronic address: [email protected].
PMID: 41605734 DOI: 10.1016/j.bja.2025.11.058
Abstract

Background: Sevoflurane increases surface expression of α5 subunit-containing γ-aminobutyric acid type A receptors (GABAAR-α5) and tonic currents in the hippocampus, contributing to postoperative memory decline. We investigated sevoflurane modulation of the phosphorylation of the β3 subunit which co-assembles with α5 subunits following CA2+/calmodulin-dependent protein kinase II (CaMKII) activation to alter receptor trafficking and exacerbate cognitive dysfunction.

Methods: Aged C57BL/6J mice and primary hippocampal neurones were exposed to 4 vol% sevoflurane for 2 h (Sev group). Cultured neurones were transfected with a phospho-null β3 subunit (S408/409A) generated by site-directed mutagenesis. Immunoblot analysis, immunofluorescence, CA2+ imaging, whole-cell patch-clamp electrophysiological recording, pharmacological interventions, and behavioural tests were used.

Results: Sevoflurane triggered CaMKII-mediated phosphorylation at β3-S408/409, suppressing receptor internalisation and increasing surface accumulation of α5β3GABAARs (Sev vs control; P<0.0001). The β3-S408/409A double mutation abolished the enhanced surface expression of α5β3GABAARs (Sev+β3-S408/409A vs Sev+NC; P=0.0022). CaMKII inhibition with small molecule inhibitor KN-93 normalised surface upregulation of α5β3GABAARs (Sev+KN-93 vs Sev+vehicle; P<0.0001), attenuated enhanced tonic current (Sev+KN-93 vs Sev+vehicle; P=0.0027), and rescued contextual memory deficits (Sev+KN-93: 33.5% [7.3%] freezing vs Sev+vehicle: 19.3% [4.4%]; P=0.0139) induced by sevoflurane.

Conclusions: Sevoflurane disrupts α5β3GABAARs trafficking through CaMKII/β3 S408/409 phosphorylation, identifying a potential therapeutic strategy for postoperative cognitive impairment.

Keywords
CaMKII; GABA(A) receptors; cognition; perioperative neurocognitive dysfunction; sevoflurane; trafficking.
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