Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema

Abstract

Swelling of the brain or spinal cord (CNS edema) affects millions of people every year. All potential pharmacological interventions have failed in clinical trials, meaning that symptom management is the only treatment option. The water channel protein aquaporin-4 (AQP4) is expressed in astrocytes and mediates water flux across the blood-brain and blood-spinal cord barriers. Here we show that AQP4 cell-surface abundance increases in response to hypoxia-induced cell swelling in a calmodulin-dependent manner. Calmodulin directly binds the AQP4 carboxyl terminus, causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licensed drug trifluoperazine inhibited AQP4 localization to the blood-spinal cord barrier, ablated CNS edema, and led to accelerated functional recovery compared with untreated animals. We propose that targeting the mechanism of calmodulin-mediated cell-surface localization of AQP4 is a viable strategy for development of CNS edema therapies.

Publication DOI: https://doi.org/10.1016/j.cell.2020.03.037
Divisions: College of Health & Life Sciences
College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
Additional Information: © 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Funding: Biotechnology & Biosciences Research Council (to R.M.B., A.C.C., and P.K. through BB/P025927/1
Uncontrolled Keywords: AQP4,Aquaporin,TRPV4,astrocyte,calmodulin,edema,oedema,protein kinase A,spinal cord injury,traumatic brain injury,trifluoperazine,Biochemistry, Genetics and Molecular Biology(all)
Full Text Link:
Related URLs: https://linking ... 092867420303305 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2020-05-14
Accepted Date: 2020-03-18
Authors: Kitchen, Philip (ORCID Profile 0000-0002-1558-4673)
Salman, Mootaz M.
Halsey, Andrea M.
Clarke-bland, Charlotte
Macdonald, Justin A.
Ishida, Hiroaki
Vogel, Hans J.
Almutiri, Sharif
Logan, Ann
Kreida, Stefan
Al-jubair, Tamim
Winkel Missel, Julie
Gourdon, Pontus
Törnroth-horsefield, Susanna
Conner, Matthew T.
Ahmed, Zubair
Conner, Alex C.
Bill, Roslyn M. (ORCID Profile 0000-0003-1331-0852)

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