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

Research output: Contribution to journalJournal articleResearchpeer-review

  • 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
  • Gourdon, Pontus Emanuel
  • Susanna Törnroth-Horsefield
  • Matthew T. Conner
  • Zubair Ahmed
  • Alex C. Conner
  • Roslyn M. Bill

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 languageEnglish
JournalCell
Volume181
Issue number4
Pages (from-to)784-799
ISSN0092-8674
DOIs
Publication statusPublished - 2020

    Research areas

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

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