Yool Andrea J
Departments of Physiology and Pharmacology, The BIO5 Institute, Tucson AZ, USA.
Curr Pharm Des. 2007;13(31):3212-21. doi: 10.2174/138161207782341349.
Aquaporins (AQPs) are expressed in physiologically essential tissues and organs in which edema and fluid imbalances are of major concern. Potential roles in brain water homeostasis and edema, angiogenesis, cell migration, development, neuropathological diseases, and cancer suggest that this family of membrane proteins is an attractive set of novel drug targets. A problem in pursuing therapeutic and basic research strategies for dissecting contributions of AQPs to cell and tissue functions is that little is known regarding the pharmacology of AQP channels; currently defined agents such as tetraethylammonium and phloretin as blockers for aquaporins suffer from a lack of specificity and potency. Subtypes of AQPs modulated by signaling pathways could enable discrete localized control of fluid homeostasis, volume and morphology in cells and intracellular organelles, and might be found to participate in many different aspects of physiology, such as the control of paracellular permeability, process extension, growth, migration, and other responses involving changes in cell shape or surface to volume ratios. Recognizing that AQP1 is a water channel and, under permissive conditions, also a cGMP-gated cation channel, evidence in various tissues for a coupling of the cGMP signaling cascade to a physiological outcome that might involve AQP1 dual ion-and-water channel functions is of interest. Groundbreaking advances in defining aquaporin gating mechanisms suggest conformational changes are important elements in regulation and gating across classes of aquaporins. With a rapidly expanding knowledge of aquaporin structure and functional regulation, new avenues for manipulation of aquaporin channels are likely to be discovered. In parallel, a discovery for novel compounds with specificity and potency for aquaporins is a compelling goal. The need for pharmacological agents to dissect the roles of aquaporins in physiological and pathological processes is a clear call for further research in the field.
水通道蛋白（AQPs）在生理上至关重要的组织和器官中表达，而这些组织和器官中水肿和液体失衡是主要关注点。其在脑水稳态与水肿、血管生成、细胞迁移、发育、神经病理疾病以及癌症中的潜在作用表明，这类膜蛋白家族是一组极具吸引力的新型药物靶点。在探索剖析AQPs对细胞和组织功能贡献的治疗和基础研究策略时，一个问题是对AQP通道的药理学了解甚少；目前定义的诸如四乙铵和根皮素等作为水通道蛋白阻滞剂的药物缺乏特异性和效力。由信号通路调节的AQPs亚型能够实现对细胞和细胞内细胞器中液体稳态、体积和形态的离散局部控制，并且可能参与生理学的许多不同方面，例如对细胞旁通透性的控制、突起延伸、生长、迁移以及其他涉及细胞形状或表面积与体积比变化的反应。认识到AQP1是一种水通道，并且在允许的条件下也是一种cGMP门控阳离子通道，各种组织中关于cGMP信号级联与可能涉及AQP1双离子和水通道功能的生理结果之间偶联的证据很有意思。在定义水通道蛋白门控机制方面的突破性进展表明，构象变化是跨水通道蛋白类别进行调节和门控的重要因素。随着对水通道蛋白结构和功能调节的认识迅速扩展，可能会发现操纵水通道蛋白通道的新途径。同时，发现对水通道蛋白具有特异性和效力的新型化合物是一个引人注目的目标。需要药理学试剂来剖析水通道蛋白在生理和病理过程中的作用，这明确呼吁在该领域进行进一步研究。
