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

Kitchen, Philip ; Salman, Mootaz M. ; Halsey, Andrea M. ; Clarke-Bland, Charlotte ; MacDonald, Justin A. ; Ishida, Hiroaki ; Vogel, Hans J. ; Almutiri, Sharif ; Logan, Ann and Kreida, Stefan LU , et al. (2020) In Cell 181(4). p.19-799
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... (More)

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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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AQP4, Aquaporin, astrocyte, calmodulin, edema, oedema, protein kinase A, spinal cord injury, traumatic brain injury, trifluoperazine, TRPV4
in
Cell
volume
181
issue
4
pages
19 - 799
publisher
Cell Press
external identifiers
  • scopus:85084376702
  • pmid:32413299
ISSN
0092-8674
DOI
10.1016/j.cell.2020.03.037
language
English
LU publication?
yes
id
0c0a5133-27c6-4f59-968f-f1e33afb47b6
date added to LUP
2020-06-03 12:31:00
date last changed
2024-06-27 18:32:24
@article{0c0a5133-27c6-4f59-968f-f1e33afb47b6,
  abstract     = {{<p>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.</p>}},
  author       = {{Kitchen, Philip and Salman, Mootaz M. and Halsey, Andrea M. and Clarke-Bland, Charlotte and MacDonald, Justin A. and Ishida, Hiroaki and Vogel, Hans J. and Almutiri, Sharif and Logan, Ann and Kreida, Stefan and Al-Jubair, Tamim and Winkel Missel, Julie and Gourdon, Pontus and Törnroth-Horsefield, Susanna and Conner, Matthew T. and Ahmed, Zubair and Conner, Alex C. and Bill, Roslyn M.}},
  issn         = {{0092-8674}},
  keywords     = {{AQP4; Aquaporin; astrocyte; calmodulin; edema; oedema; protein kinase A; spinal cord injury; traumatic brain injury; trifluoperazine; TRPV4}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{19--799}},
  publisher    = {{Cell Press}},
  series       = {{Cell}},
  title        = {{Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema}},
  url          = {{http://dx.doi.org/10.1016/j.cell.2020.03.037}},
  doi          = {{10.1016/j.cell.2020.03.037}},
  volume       = {{181}},
  year         = {{2020}},
}