Journal
CELL
Volume 181, Issue 4, Pages 784-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2020.03.037
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Funding
- Biotechnology & Biosciences Research Council [BB/P025927/1]
- Aston University
- Biogen
- International Spinal Research Trust [NRB116]
- Saudi Education Ministry in London [SHU11]
- Swedish Research Council [2013-05945]
- Crafoord Foundation [20140811, 20180916]
- Magnus Bergvall Foundation [2015-01534]
- Knut and Alice Wallenburg Foundation
- Lundbeck Foundation
- Natural Sciences and Engineering Research Council of Canada
- BBSRC [BB/P025927/1] Funding Source: UKRI
- Swedish Research Council [2013-05945] Funding Source: Swedish Research Council
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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.
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