Kitchen, PSalman, MMHalsey, AMClarke-Bland, CMacDonald, JAIshida, HVogel, HJAlmutiri, SLogan, AKreida, SAl-Jubair, TWinkel Missel, JGourdon, PTörnroth-Horsefield, SConner, MTAhmed, ZConner, ACBill, RM2020-07-012020-07-012020-05-14Kitchen, 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.e19.0092-867432413299 (pubmed)10.1016/j.cell.2020.03.037http://hdl.handle.net/2436/623314© 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© 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.application/pdfenLicence for published version: Creative Commons Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/AQP4aquaporinTRPV4astrocytecalmodulinedemaoedemaprotein kinase Aspinal cord injurytraumatic brain injurytrifluoperazineJournal article1097-4172Cell2020-06-25