英国阿斯顿大学额Roslyn M. Bill和英国伯明翰大学Alex C. Conner、Zubair Ahmed研究团队合作发现，靶向Aquaporin-4（AQP4）亚细胞定位可治疗中枢神经系统（CNS）水肿。这一研究成果发表在2020年5月14日的《细胞》上。
他们显示，AQP4细胞表面丰度增加，以钙调蛋白依赖性方式响应缺氧诱导的细胞肿胀。钙调蛋白直接结合AQP4羧基末端，引起特定的构象变化并驱动AQP4细胞表面定位。与未经治疗的动物相比，用许可的药物三氟拉嗪在大鼠脊髓损伤模型中抑制钙调蛋白，可抑制AQP4定位于血脊髓屏障，减轻CNS水肿，并导致功能恢复加快。他们建议针对钙调蛋白介导的AQP4的细胞表面定位的机制，是发展CNS水肿疗法的可行策略。
研究人员表示，每年，脑部或脊髓肿胀都会影响数百万人。所有潜在的药理干预措施在临床试验中均告失败，这意味着症状管理是唯一的治疗选择。水通道蛋白AQP4在星形胶质细胞中表达，并介导水流穿过血脑和血脊髓屏障。
附：英文原文
Title: Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema
Author: 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, Pontus Gourdon, Susanna Trnroth-Horsefield, Matthew T. Conner, Zubair Ahmed, Alex C. Conner, Roslyn M. Bill
Issue&Volume: 2020/05/14
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 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.
DOI: 10.1016/j.cell.2020.03.037
Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30330-5