Targeting Aquaporin-4 subcellular localization to treat central nervous system edema
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Winkel Missel, J
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Abstract© 2020 The Author(s) 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.
CitationKitchen, P., Salman, M.M., Halsey, A.M. et al.(2020) Targeting Aquaporin-4 subcellular localization to treat central nervous system edema, Cell, 181(4), pp. 784-799.e19.
PubMed ID32413299 (pubmed)
Description© 2020 The Authors. Published by Elsevier. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1016/j.cell.2020.03.037
Except where otherwise noted, this item's license is described as Licence for published version: Creative Commons Attribution 4.0 International
- Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema.
- Authors: Kitchen P, Salman MM, Halsey AM, Clarke-Bland C, MacDonald JA, Ishida H, Vogel HJ, Almutiri S, Logan A, Kreida S, Al-Jubair T, Winkel Missel J, Gourdon P, Törnroth-Horsefield S, Conner MT, Ahmed Z, Conner AC, Bill RM
- Issue date: 2020 May 14
- Inhibiting High Mobility Group Box-1 Reduces Early Spinal Cord Edema and Attenuates Astrocyte Activation and Aquaporin-4 Expression after Spinal Cord Injury in Rats.
- Authors: Sun L, Li M, Ma X, Zhang L, Song J, Lv C, He Y
- Issue date: 2019 Feb 1
- Hypothermia increases aquaporin 4 (AQP4) plasma membrane abundance in human primary cortical astrocytes via a calcium/transient receptor potential vanilloid 4 (TRPV4)- and calmodulin-mediated mechanism.
- Authors: Salman MM, Kitchen P, Woodroofe MN, Brown JE, Bill RM, Conner AC, Conner MT
- Issue date: 2017 Nov
- Inhibition of HMGB1 reduces rat spinal cord astrocytic swelling and AQP4 expression after oxygen-glucose deprivation and reoxygenation via TLR4 and NF-κB signaling in an IL-6-dependent manner.
- Authors: Sun L, Li M, Ma X, Feng H, Song J, Lv C, He Y
- Issue date: 2017 Nov 25