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Cited by 452Ion Transport and Channel RegulationBarrier Structure and Function StudiesCerebrospinal fluid and hydrocephalus

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

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Kitchen, Philip, Salman, Mootaz M., Halsey, Andrea M., Clarke-Bland, Charlotte, MacDonald, Justin A., Ishida, Hiroaki, Vogel, Hans J., Almutiri, Sharif +10 more·2020·Cell
DOI 10.1016/j.cell.2020.03.037PMC PMC7242911
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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.

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  • Under pathological conditions, astrocytes undergo reactive astrogliosis characterized by morphological and functional changes such as hypertrophy, process elongation, up-regulation of GFAP, or dynamic relocalization of proteins such as aquaporin-4.

    “Under pathological conditions, they undergo reactive astrogliosis, characterized by morphological and functional changes such as hypertrophy, process elongation, up-regulation of glial fibrillary acidic protein (GFAP) (2–5), or dynamic relocalization of proteins such as aquaporin-4 (6, 7).”

    From Varicose projection astrocytes: Conserved reactive cells in brain pathology (2026) · cites this paper as [6]

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Authors
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.
Affiliations
  • Aston University (GB)
  • University of Mosul (IQ)
  • University of Birmingham (GB)
  • University of Calgary (CA)
  • Shaqra University (SA)
  • Lund University (SE)
  • University of Copenhagen (DK)
  • University of Wolverhampton (GB)
Corresponding author
  • Ahmed, Zubair
  • Conner, Alex C.
  • Bill, Roslyn M.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2020-05
Volume
181
Issue
4
Pages
784-799.e19
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2020.03.037
PMC
PMC7242911
OpenAlex
W3025713031
Cited by
452
References
4
Citations by year
2026: 49 · 2025: 63 · 2024: 67 · 2023: 76 · 2022: 97 · 2021: 83 · 2020: 17
FWCI
22.14
Type
journal article
Language
en
Open access
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  • Cell (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • Aston Publications Explorer (Aston University) (acceptedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
  • Lund University Publications (Lund University) (submittedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
  • Wolverhampton Intellectual Repository and E-Theses (University of Wolverhampton) (submittedVersion, cc-by)
Funders
  • Vetenskapsrådet
  • Crafoordska Stiftelsen
  • Ministry of Education – Kingdom of Saudi Arabi
  • Magnus Bergvalls Stiftelse
  • Aston University
  • International Spinal Research Trust
  • Biotechnology and Biological Sciences Research Council
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
Keywords
aquaporin-4, calmodulin, cell swelling, hypoxia, astrocytes, blood-spinal cord barrier, blood-brain barrier, spinal cord injury, trifluoperazine, water channel proteins, functional recovery
MeSH terms
Animals, Astrocytes, Brain, Brain Edema, Calmodulin, Central Nervous System, Edema, Male, Spinal Cord, Spinal Cord Injuries, Trifluoperazine, Rats, Sprague-Dawley, Rats, Aquaporin 4

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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