Targeting aquaporin-4 subcellular localization as a novel approach to treat CNS edema
Research output: Contribution to journal › Article › peer-review
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.
|Publication status||Published - 14 May 2020|
- aquaporin, AQP4, edema, astrocyte, spinal cord injury, traumatic brain injury, trifluoperazine, calmodulin, protein kinase A, TRPV4, oedema