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

Philip Kitchen, Mootaz M. Salman, Andrea M. Halsey, Charlotte Clarke-bland, Justin A. Macdonald, Hiroaki Ishida, Hans J. Vogel, Sharif Almutiri, Ann Logan, Stefan Kreida, Tamim Al-jubair, Julie Winkel Missel, Pontus Gourdon, Susanna Törnroth-horsefield, Matthew T. Conner, Zubair Ahmed, Alex C. Conner, Roslyn M. Bill*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)784-799.e19
JournalCell
Volume181
Issue number4
DOIs
Publication statusPublished - 14 May 2020

Bibliographical note

© 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

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    Kitchen, P., Salman, M. M., Halsey, A. M., Clarke-bland, C., Macdonald, J. A., Ishida, H., Vogel, H. J., Almutiri, S., Logan, A., Kreida, S., Al-jubair, T., Winkel Missel, J., Gourdon, P., Törnroth-horsefield, S., Conner, M. T., Ahmed, Z., Conner, A. C., & Bill, R. M. (2020). Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema. Cell, 181(4), 784-799.e19. https://doi.org/10.1016/j.cell.2020.03.037