Targeting aquaporin-4 subcellular localization as a novel approach to treat CNS edema

Research output: Contribution to journalArticle

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Targeting aquaporin-4 subcellular localization as a novel approach to treat CNS edema. / Kitchen, Philip; Salman, Mootaz M.; Halsey, Andrea; Clarke-Band, Charlotte; MacDonald, Justin; Ishida, Hiroaki; Vogel, Hans; Almuitiri, Sharif; Logan, Ann; Kreida, Stefan; Al-Jubair, Tamim; Missel, Julie; Gourdon, Pontus; Tornroth-Horsefield, Suzanna; Conner, Matthew; Ahmed, Zubair; Conner, Alex; Bill, Roslyn M.

In: Cell, Vol. 181, No. 4, 14.05.2020, p. 784-799.e19.

Research output: Contribution to journalArticle

Harvard

Kitchen, P, Salman, MM, Halsey, A, Clarke-Band, C, MacDonald, J, Ishida, H, Vogel, H, Almuitiri, S, Logan, A, Kreida, S, Al-Jubair, T, Missel, J, Gourdon, P, Tornroth-Horsefield, S, Conner, M, Ahmed, Z, Conner, A & Bill, RM 2020, 'Targeting aquaporin-4 subcellular localization as a novel approach to treat CNS edema', Cell, vol. 181, no. 4, pp. 784-799.e19. https://doi.org/10.1016/j.cell.2020.03.037

APA

Kitchen, P., Salman, M. M., Halsey, A., Clarke-Band, C., MacDonald, J., Ishida, H., Vogel, H., Almuitiri, S., Logan, A., Kreida, S., Al-Jubair, T., Missel, J., Gourdon, P., Tornroth-Horsefield, S., Conner, M., Ahmed, Z., Conner, A., & Bill, R. M. (2020). Targeting aquaporin-4 subcellular localization as a novel approach to treat CNS edema. Cell, 181(4), 784-799.e19. https://doi.org/10.1016/j.cell.2020.03.037

Vancouver

Kitchen P, Salman MM, Halsey A, Clarke-Band C, MacDonald J, Ishida H et al. Targeting aquaporin-4 subcellular localization as a novel approach to treat CNS edema. Cell. 2020 May 14;181(4):784-799.e19. https://doi.org/10.1016/j.cell.2020.03.037

Author

Kitchen, Philip ; Salman, Mootaz M. ; Halsey, Andrea ; Clarke-Band, Charlotte ; MacDonald, Justin ; Ishida, Hiroaki ; Vogel, Hans ; Almuitiri, Sharif ; Logan, Ann ; Kreida, Stefan ; Al-Jubair, Tamim ; Missel, Julie ; Gourdon, Pontus ; Tornroth-Horsefield, Suzanna ; Conner, Matthew ; Ahmed, Zubair ; Conner, Alex ; Bill, Roslyn M. / Targeting aquaporin-4 subcellular localization as a novel approach to treat CNS edema. In: Cell. 2020 ; Vol. 181, No. 4. pp. 784-799.e19.

Bibtex

@article{08507fd76e6c4205928d01b46c3aace7,
title = "Targeting aquaporin-4 subcellular localization as a novel approach to treat CNS edema",
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 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 carboxy-terminus causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licenced 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 the development of novel CNS edema therapies.",
keywords = "aquaporin, AQP4, edema, astrocyte, spinal cord injury, traumatic brain injury, trifluoperazine, calmodulin, protein kinase A, TRPV4, oedema",
author = "Philip Kitchen and Salman, {Mootaz M.} and Andrea Halsey and Charlotte Clarke-Band and Justin MacDonald and Hiroaki Ishida and Hans Vogel and Sharif Almuitiri and Ann Logan and Stefan Kreida and Tamim Al-Jubair and Julie Missel and Pontus Gourdon and Suzanna Tornroth-Horsefield and Matthew Conner and Zubair Ahmed and Alex Conner and Bill, {Roslyn M}",
year = "2020",
month = may,
day = "14",
doi = "10.1016/j.cell.2020.03.037",
language = "English",
volume = "181",
pages = "784--799.e19",
journal = "Cell",
issn = "0092-8674",
publisher = "Elsevier",
number = "4",

}

RIS

TY - JOUR

T1 - Targeting aquaporin-4 subcellular localization as a novel approach to treat CNS edema

AU - Kitchen, Philip

AU - Salman, Mootaz M.

AU - Halsey, Andrea

AU - Clarke-Band, Charlotte

AU - MacDonald, Justin

AU - Ishida, Hiroaki

AU - Vogel, Hans

AU - Almuitiri, Sharif

AU - Logan, Ann

AU - Kreida, Stefan

AU - Al-Jubair, Tamim

AU - Missel, Julie

AU - Gourdon, Pontus

AU - Tornroth-Horsefield, Suzanna

AU - Conner, Matthew

AU - Ahmed, Zubair

AU - Conner, Alex

AU - Bill, Roslyn M

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 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 carboxy-terminus causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licenced 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 the development of novel CNS edema therapies.

AB - 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 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 carboxy-terminus causing a specific conformational change and driving AQP4 cell-surface localization. Inhibition of calmodulin in a rat spinal cord injury model with the licenced 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 the development of novel CNS edema therapies.

KW - aquaporin

KW - AQP4

KW - edema

KW - astrocyte

KW - spinal cord injury

KW - traumatic brain injury

KW - trifluoperazine

KW - calmodulin

KW - protein kinase A

KW - TRPV4

KW - oedema

U2 - 10.1016/j.cell.2020.03.037

DO - 10.1016/j.cell.2020.03.037

M3 - Article

VL - 181

SP - 784-799.e19

JO - Cell

JF - Cell

SN - 0092-8674

IS - 4

ER -