Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema
Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema
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DOI：
10.1016/j.cell.2020.03.037
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发表时间：
2020-05-14
期刊：
影响因子：
64.5
通讯作者：
Bill, Roslyn M.
中科院分区：
文献类型：
--
作者：
Kitchen, Philip;Salman, Mootaz M.;Bill, Roslyn M.
脑或脊髓肿胀（CNS水肿）每年影响数百万人。所有潜在的药物干预在临床试验中都失败了，这意味着症状管理是唯一的治疗选择。水通道蛋白水通道蛋白4（AQP4）在星形胶质细胞中表达，并介导穿过血脑和血脊髓屏障的水通量。在这里，我们表明，AQP4细胞表面丰度增加响应缺氧诱导的细胞肿胀钙调素依赖性的方式。钙调素直接结合AQP4羧基末端，引起特异性构象变化并驱动AQP4细胞表面定位。在大鼠脊髓损伤模型中，与未经治疗的动物相比，使用许可药物三氟拉嗪抑制钙调蛋白可抑制AQP4定位于血脊髓屏障，消融CNS水肿，并导致加速功能恢复。我们认为，针对钙调蛋白介导的AQP4细胞表面定位机制是开发CNS水肿治疗的可行策略。
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.