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

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

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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