Department of Medicine, University of California, San Francisco, CA 94143-0521, USA.
Acta Pharmacol Sin. 2011 Jun;32(6):702-10. doi: 10.1038/aps.2011.27. Epub 2011 May 9.
Aquaporin-4 (AQP4) is a water-selective transporter expressed in astrocytes throughout the central nervous system, as well as in kidney, lung, stomach and skeletal muscle. The two AQP4 isoforms produced by alternative spicing, M1 and M23 AQP4, form heterotetramers that assemble in cell plasma membranes in supramolecular structures called orthogonal arrays of particles (OAPs). Phenotype analysis of AQP4-null mice indicates the involvement of AQP4 in brain and spinal cord water balance, astrocyte migration, neural signal transduction and neuroinflammation. AQP4-null mice manifest reduced brain swelling in cytotoxic cerebral edema, but increased brain swelling in vasogenic edema and hydrocephalus. AQP4 deficiency also increases seizure duration, impairs glial scarring, and reduces the severity of autoimmune neuroinflammation. Each of these phenotypes is likely explicable on the basis of reduced astrocyte water permeability in AQP4 deficiency. AQP4 is also involved in the neuroinflammatory demyelinating disease neuromyelitis optica (NMO), where autoantibodies (NMO-IgG) targeting AQP4 produce astrocyte damage and inflammation. Mice administered NMO-IgG and human complement by intracerebral injection develop characteristic NMO lesions with neuroinflammation, demyelination, perivascular complement deposition and loss of glial fibrillary acidic protein and AQP4 immunoreactivity. Our findings suggest the potential utility of AQP4-based therapeutics, including small-molecule modulators of AQP4 water transport function for therapy of brain swelling, injury and epilepsy, as well as small-molecule or monoclonal antibody blockers of NMO-IgG binding to AQP4 for therapy of NMO.
水通道蛋白 4(AQP4)是一种在中枢神经系统的星形胶质细胞中表达的水选择性转运蛋白,也在肾脏、肺、胃和骨骼肌中表达。通过选择性剪接产生的两种 AQP4 同工型,M1 和 M23 AQP4,形成异四聚体,在称为正交颗粒阵列(OAP)的超分子结构中组装在细胞质膜上。AQP4 敲除小鼠的表型分析表明 AQP4 参与了脑和脊髓的水平衡、星形胶质细胞迁移、神经信号转导和神经炎症。AQP4 敲除小鼠在细胞毒性脑水肿中表现出脑肿胀减少,但在血管源性水肿和脑积水中表现出脑肿胀增加。AQP4 缺乏还会增加癫痫发作持续时间,损害神经胶质瘢痕形成,并降低自身免疫性神经炎症的严重程度。这些表型中的每一种都可能基于 AQP4 缺乏导致星形胶质细胞水通透性降低来解释。AQP4 还参与了神经炎症性脱髓鞘疾病视神经脊髓炎(NMO),其中针对 AQP4 的自身抗体(NMO-IgG)导致星形胶质细胞损伤和炎症。通过脑内注射给予 NMO-IgG 和人补体的小鼠会发展出具有神经炎症、脱髓鞘、血管周围补体沉积以及神经胶质纤维酸性蛋白和 AQP4 免疫反应性丧失的特征性 NMO 病变。我们的研究结果表明,基于 AQP4 的治疗方法具有潜在的应用价值,包括小分子调节剂 AQP4 水转运功能治疗脑水肿、损伤和癫痫,以及小分子或单克隆抗体阻断 NMO-IgG 与 AQP4 的结合治疗 NMO。