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

Research output: Contribution to journal › Journal article › Research › peer-review

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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; Kreida, Stefan; Al-Jubair, Tamim; Winkel Missel, Julie; Gourdon, Pontus; Törnroth-Horsefield, Susanna; Conner, Matthew T.; Ahmed, Zubair; Conner, Alex C.; Bill, Roslyn M.

In: Cell, Vol. 181, No. 4, 2020, p. 784-799.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

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. https://doi.org/10.1016/j.cell.2020.03.037

APA

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. https://doi.org/10.1016/j.cell.2020.03.037

Vancouver

Kitchen P, Salman MM, Halsey AM, Clarke-Bland C, MacDonald JA, Ishida H et al. Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema. Cell. 2020;181(4):784-799. https://doi.org/10.1016/j.cell.2020.03.037

Author

Kitchen, Philip ; Salman, Mootaz M. ; Halsey, Andrea M. ; Clarke-Bland, Charlotte ; MacDonald, Justin A. ; Ishida, Hiroaki ; Vogel, Hans J. ; Almutiri, Sharif ; Logan, Ann ; Kreida, Stefan ; Al-Jubair, Tamim ; Winkel Missel, Julie ; Gourdon, Pontus ; Törnroth-Horsefield, Susanna ; Conner, Matthew T. ; Ahmed, Zubair ; Conner, Alex C. ; Bill, Roslyn M. / Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema. In: Cell. 2020 ; Vol. 181, No. 4. pp. 784-799.

Bibtex

@article{3a393df171254203987bc508ddd7acf4,
title = "Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System 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 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.",
keywords = "AQP4, Aquaporin, astrocyte, calmodulin, edema, oedema, protein kinase A, spinal cord injury, traumatic brain injury, trifluoperazine, TRPV4",
author = "Philip Kitchen and Salman, {Mootaz M.} and Halsey, {Andrea M.} and Charlotte Clarke-Bland and MacDonald, {Justin A.} and Hiroaki Ishida and Vogel, {Hans J.} and Sharif Almutiri and Ann Logan and Stefan Kreida and Tamim Al-Jubair and {Winkel Missel}, Julie and Pontus Gourdon and Susanna T{\"o}rnroth-Horsefield and Conner, {Matthew T.} and Zubair Ahmed and Conner, {Alex C.} and Bill, {Roslyn M.}",
year = "2020",
doi = "10.1016/j.cell.2020.03.037",
language = "English",
volume = "181",
pages = "784--799",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",

}

RIS

TY - JOUR

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.

PY - 2020

Y1 - 2020

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.

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 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.

KW - AQP4

KW - Aquaporin

KW - astrocyte

KW - calmodulin

KW - edema

KW - oedema

KW - protein kinase A

KW - spinal cord injury

KW - traumatic brain injury

KW - trifluoperazine

KW - TRPV4

UR - http://www.scopus.com/inward/record.url?scp=85084376702&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2020.03.037

DO - 10.1016/j.cell.2020.03.037

M3 - Journal article

C2 - 32413299

AN - SCOPUS:85084376702

VL - 181

SP - 784

EP - 799

JO - Cell

JF - Cell

SN - 0092-8674

IS - 4

ER -

ID: 244572531