Aquaporin Function: Seek and You Shall Find!
Aquaporin Function: Seek and You Shall Find!
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DOI：
10.1093/function/zqaa041
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发表时间：
2021
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通讯作者：
Brown D
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作者：
Brown D
早在彼得·阿格雷等人之前。发现了第一个水通道蛋白AQP1，当时称为CHIP28 1。人们了解到，蛋白质水通道参与了渗透压驱动的水在生物膜上的快速移动。近30年后，我怀疑，就连他也没有预料到水通道蛋白研究的指数级增长，这导致在哺乳动物中发现了13个水通道蛋白，在进化规模较低的物种、原核生物和植物界中发现了数十个水通道蛋白。除了它们的绝对数量，我想知道他是否也预见到这些明显简单的水通道参与了如此庞大的一系列细胞过程，以及似乎无穷无尽的小分子和离子(例如尿素、甘油、甘露醇、山梨醇、氨塔4、过氧化氢、氯±、NO±3、亚砷酸盐)的跨膜运动，甚至气体2(例如二氧化碳、NH3、H2S、O2、NO)。早期的研究很快确定了一些家族成员(水甘油疏松素)在甘油和尿素以及水的运输中的作用。但多年来，各种水通道蛋白的通透性如此之大，以至于人们不得不问，在表达这些蛋白的众多细胞类型中，许多这些蛋白最关键和最重要的生理作用是什么(S)。事实上，一些“水”孔蛋白的透水性相对较低，这表明它们的主要功能在其他地方：例如，AQP0、AQP3、AQP6、AQP7，以及哺乳动物家族中分歧最大的成员AQP11和12。具有“兼职”功能的水通道蛋白--在某些情况下与透水性没有明显关系--正在迅速增加，这引发了更多关于其主要生理作用的问题。一些细胞类型甚至在同一膜上表达多个水通道蛋白家族成员。例如，肾脏集合管某些区域的主细胞在其基底外侧质膜上共同表达AQP2、AQP3和AQP4-显然这不是仅对水的通透性所必需的。事实上，AQP4基因敲除对整体尿液浓度几乎没有影响，沙漠鼠--以拥有哺乳动物王国中最发达的浓缩机制而闻名--根本不在它们的肾脏中表达AQP4。相比之下，许多研究证实了AQP2在肾脏重吸收水分中的关键作用4；AQP2功能突变的丢失会导致常染色体肾源性尿崩症--一种尿浓缩能力的丧失。在许多情况下，许多水通道蛋白在正常组织和器官生理学中的难以捉摸的作用还没有具体确定，甚至通过使用AQP基因敲除小鼠也是如此，这些小鼠通常(但并不总是)没有或表现出轻微的表型。然而，越来越多的体内和体外研究表明，水通道蛋白与正常生理和疾病状态有关，而这些状态通常与其通道活性没有实验上的相关性。例如，水通道蛋白参与细胞迁移、上皮和器官发育、肥胖、炎症、癌症进展以及包括阿尔茨海默病在内的各种神经退行性疾病。促进水和溶质跨膜移动确实可能参与了这些过程，但水通道蛋白的其他特征也可能发挥重要作用--例如它们参与蛋白质与细胞骨架组成部分的相互作用，以及参与各种信号转导机制和其他细胞内途径。因此，理解水通道蛋白功能的生理重要性是一项持续的探索；仅有几个…强调了这项任务的艰巨性。
Long before Peter Agre et al. discovered the first aquaporin, AQP1, then called CHIP28 1 it was understood that proteinaceous water channels were involved in rapid, osmotically-driven water movement across biological membranes. Almost 30 years later, I suspect that even he did not anticipate the exponential growth in aquaporin research that has led to the discovery of 13 aquaporins in mammals, and dozens more in species lower on the evolutionary scale, in procaryotes, and in the plant kingdom. More than their sheer number, I wonder if he also foresaw the involvement of these apparently simple water channels in such a vast array of cellular processes, and in the transmembrane movement of a seemingly endless list of small molecules and ions (eg, urea, glycerol, mannitol, sorbitol, NHþ 4, H2O2, ClÀ, NOÀ 3, arsenite), and even gases 2 (eg, CO2, NH3, H2S, O2, NO). Early studies quickly established a role for some family members (the aquaglyceroporins) in the transport of glycerol and urea in addition to water. But there has been such an expansion of permeability properties of various aquaporins reported over the years that one is left to ask what is the most critical and important physiological role (s) of many of these proteins in the multitude of cell types in which they are expressed. Indeed, some “aqua” porins have a relatively low water permeability, indicating that their principal function lies elsewhere: AQP0, AQP3, AQP6, AQP7, for example, as well as the most divergent members of the mammalian family, AQP11 and 12. The list of aquaporins with “moonlighting” functions—in some cases not obviously related to water permeability—is growing rapidly, leading to still more questions regarding their primary physiological roles. Some cell types even express multiple aquaporin family members in the same membrane. For example, principal cells in some regions of the kidney collecting duct coexpress AQP2, AQP3, and AQP4 in their basolateral plasma membrane—clearly this is not necessary for water permeability alone. Indeed AQP4 knockout has little effect on overall urine concentration, and desert rats—famous for having the most highly developed concentrating mechanism in the mammalian kingdom—do not express AQP4 at all in their kidneys 3! In contrast, many studies have confirmed the critical role of AQP2 in water reabsorption by the kidney 4; loss of function mutations in AQP2 causes autosomal nephrogenic diabetes insipidus—a loss of urinary concentrating capacity. In many cases, the elusive role of many aquaporins in normal tissue and organ physiology has not been specifically determined, even by the use of AQP knockout mice, which often (but not always) show no or minor phenotypes. However, an increasing number of studies both in vivo and in vitro implicate aquaporins in normal physiology and disease states that have often not been experimentally correlated with their channel activity. For example, aquaporins are involved in events such as cell migration, epithelial, and organ development, obesity, inflammation, cancer progression, and various neurodegenerative diseases, including Alzheimer’s disease. Facilitating water and solute movement across membranes might indeed be involved in these processes, but other features of the aquaporin proteins could also play an important role—such as their participation in protein–protein interactions with components of the cytoskeleton, as well as with various signal transduction mechanisms and other intracellular pathways. 5 Understanding the physiological importance of aquaporin function is, therefore, an ongoing quest; the enormity of the task is highlighted by just a few …