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

Research output: Contribution to journalArticle

Authors

  • Philip Kitchen
  • Mootaz M. Salman
  • Andrea Halsey
  • Charlotte Clarke-Band
  • Justin MacDonald
  • Hiroaki Ishida
  • Hans Vogel
  • Sharif Almuitiri
  • Stefan Kreida
  • Tamim Al-Jubair
  • Julie Missel
  • Pontus Gourdon
  • Suzanna Tornroth-Horsefield
  • Matthew Conner
  • Roslyn M Bill

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)784-799.e19
JournalCell
Volume181
Issue number4
Publication statusPublished - 14 May 2020

Keywords

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