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

Philip Kitchen; Mootaz M. Salman; Andrea M. Halsey; Charlotte Clarke-bland; Justin A. Macdonald; Hiroaki Ishida; Hans J. Vogel; Sharif Almutiri; Ann Logan; Stefan Kreida; Tamim Al-jubair; Julie Winkel Missel; Pontus Gourdon; Susanna Törnroth-horsefield; Matthew T. Conner; Zubair Ahmed; Alex C. Conner; Roslyn M. Bill

doi:10.1016/j.cell.2020.03.037

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

Philip Kitchen, Mootaz M. Salman, Andrea M. Halsey, Charlotte Clarke-bland, Justin A. Macdonald, Hiroaki Ishida, Hans J. Vogel, Sharif Almutiri, Ann Logan, Stefan Kreida, Tamim Al-jubair, Julie Winkel Missel, Pontus Gourdon, Susanna Törnroth-horsefield, Matthew T. Conner, Zubair Ahmed, Alex C. Conner, Roslyn M. Bill^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	784-799.e19
Journal	Cell
Volume	181
Issue number	4
DOIs	https://doi.org/10.1016/j.cell.2020.03.037
Publication status	Published - 14 May 2020

Bibliographical note

© 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Funding: Biotechnology & Biosciences Research Council (to R.M.B., A.C.C., and P.K. through BB/P025927/1

Keywords

AQP4
Aquaporin
TRPV4
astrocyte
calmodulin
edema
oedema
protein kinase A
spinal cord injury
traumatic brain injury
trifluoperazine

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10.1016/j.cell.2020.03.037Licence: CC BY 3.0

Targeting Aquaporin-4 Subcellular Localization
© 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
Final published version, 6.76 MBLicence: CC BY 3.0

Cite this

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. (2020). Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema. Cell, 181(4), 784-799.e19. https://doi.org/10.1016/j.cell.2020.03.037

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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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note = "{\textcopyright} 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Funding: Biotechnology & Biosciences Research Council (to R.M.B., A.C.C., and P.K. through BB/P025927/1",

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doi = "10.1016/j.cell.2020.03.037",

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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 2020, 'Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema', Cell, vol. 181, no. 4, pp. 784-799.e19. https://doi.org/10.1016/j.cell.2020.03.037

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T1 - Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema

AU - Kitchen, Philip

AU - Salman, Mootaz M.

AU - Halsey, Andrea M.

AU - Clarke-bland, Charlotte

AU - Macdonald, Justin A.

AU - Ishida, Hiroaki

AU - Vogel, Hans J.

AU - Almutiri, Sharif

AU - Logan, Ann

AU - Kreida, Stefan

AU - Al-jubair, Tamim

AU - Winkel Missel, Julie

AU - Gourdon, Pontus

AU - Törnroth-horsefield, Susanna

AU - Conner, Matthew T.

AU - Ahmed, Zubair

AU - Conner, Alex C.

AU - Bill, Roslyn M.

N1 - © 2020 The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) Funding: Biotechnology & Biosciences Research Council (to R.M.B., A.C.C., and P.K. through BB/P025927/1

PY - 2020/5/14

Y1 - 2020/5/14

N2 - 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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KW - Aquaporin

KW - TRPV4

KW - astrocyte

KW - calmodulin

KW - edema

KW - oedema

KW - protein kinase A

KW - spinal cord injury

KW - traumatic brain injury

KW - trifluoperazine

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U2 - 10.1016/j.cell.2020.03.037

DO - 10.1016/j.cell.2020.03.037

M3 - Article

SN - 0092-8674

VL - 181

SP - 784-799.e19

JO - Cell

JF - Cell

IS - 4

ER -

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

Abstract

Bibliographical note

Keywords

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