生物
中枢神经系统
三氟拉嗪
水通道蛋白
脊髓
钙调蛋白
运动性
水通道蛋白4
药理学
脊髓损伤
水肿
神经科学
细胞生物学
生物化学
内科学
酶
医学
作者
Philip Kitchen,Mootaz M. Salman,Andrea Halsey,Charlotte Clarke-Bland,Justin A. MacDonald,Hiroaki Ishida,Hans J. Vogel,Sharif Almutiri,Ann Logan,Stefan Kreida,Tamim Al-Jubair,Julie Winkel Missel,Pontus Gourdon,Susanna Törnroth‐Horsefield,Matthew Conner,Zubair Ahmed,Alex C. Conner,Roslyn M. Bill
出处
期刊:Cell
[Elsevier]
日期:2020-05-01
卷期号:181 (4): 784-799.e19
被引量:282
标识
DOI:10.1016/j.cell.2020.03.037
摘要
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.
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