Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema.,Cell

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Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema.
Cell ( IF 45.5 ) Pub Date : 2020-05-14 , DOI: 10.1016/j.cell.2020.03.037
Philip Kitchen ₁ , Mootaz M Salman ₂ , Andrea M Halsey ₃ , Charlotte Clarke-Bland ₁ , Justin A MacDonald ₄ , Hiroaki Ishida ₅ , Hans J Vogel ₆ , Sharif Almutiri ₇ , Ann Logan ₃ , Stefan Kreida ₈ , Tamim Al-Jubair ₈ , Julie Winkel Missel ₉ , Pontus Gourdon ₁₀ , Susanna Törnroth-Horsefield ₈ , Matthew T Conner ₁₁ , Zubair Ahmed ₃ , Alex C Conner ₁₂ , Roslyn M Bill ₁

Affiliation

School of Life & Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pharmacology, College of Pharmacy, University of Mosul, Mosul 41002, Iraq.
Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada.
Department of Biological Sciences, University of Calgary, Calgary, AB T2N 4N1, Canada.
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada; Department of Biological Sciences, University of Calgary, Calgary, AB T2N 4N1, Canada.
Neuroscience and Ophthalmology, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Department of Clinical Laboratory Science, College of Applied Medical Science, Shaqra University, Shaqra, Saudi Arabia.
Department of Biochemistry and Structural Biology, Lund University, PO Box 124, 221 00 Lund, Sweden.
Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Experimental Medical Science, Lund University, PO Box 118, 221 00 Lund, Sweden.
School of Sciences, Research Institute in Healthcare Science, University of Wolverhampton, Wolverhampton WV1 1LY, UK.
Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

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.

中文翻译：

靶向 Aquaporin-4 亚细胞定位治疗中枢神经系统水肿。

大脑或脊髓肿胀（中枢神经系统水肿）每年影响数百万人。所有潜在的药物干预措施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，介导水流穿过血脑和血脊髓屏障。在这里，我们发现 AQP4 细胞表面丰度以钙调蛋白依赖性方式响应缺氧诱导的细胞肿胀而增加。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。在大鼠脊髓损伤模型中，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，消除中枢神经系统水肿，并与未经治疗的动物相比加速功能恢复。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 水肿疗法的可行策略。

更新日期：2020-05-14

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