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The control of cellular water flow is mediated by the aquaporin (AQP) family of membrane proteins. The structural features of the family and the mechanism of selective water passage through the AQP pore are established, but there remains a gap in our knowledge of how water transport is regulated. Two broad possibilities exist. One is controlling the passage of water through the AQP pore, but this only has been observed as a phenomenon in some plant and microbial AQPs. An alternative is controlling the number of AQPs in the cell membrane. Here, we describe a novel pathway in mammalian cells whereby a hypotonic stimulus directly induces intracellular calcium elevations through transient receptor potential channels, which trigger AQP1 translocation. This translocation, which has a direct role in cell volume regulation, occurs within 30 s and is dependent on calmodulin activation and phosphorylation of AQP1 at two threonine residues by protein kinase C. This direct mechanism provides a rationale for the changes in water transport that are required in response to constantly changing local cellular water availability. Moreover, because calcium is a pluripotent and ubiquitous second messenger in biological systems, the discovery of its role in the regulation of AQP translocation has ramifications for diverse physiological and pathophysiological processes, as well as providing an explanation for the rapid regulation of water flow that is necessary for cell homeostasis.

Background: Aquaporin channels ensure appropriate membrane permeability to water in all cells. Results: Following a hypotonic stimulus, subcellular localization of aquaporin 1 occurs via a mechanism dependent on transient receptor potential channels, extracellular calcium influx, calmodulin, and the phosphorylation of two threonines (157 and 239) of aquaporin 1. Conclusion: Rapid translocation of aquaporin 1 regulates membrane water permeability. Significance: This mechanism may serve as a prototype for the rapid regulation of aquaporin function., The control of cellular water flow is mediated by the aquaporin (AQP) family of membrane proteins. The structural features of the family and the mechanism of selective water passage through the AQP pore are established, but there remains a gap in our knowledge of how water transport is regulated. Two broad possibilities exist. One is controlling the passage of water through the AQP pore, but this only has been observed as a phenomenon in some plant and microbial AQPs. An alternative is controlling the number of AQPs in the cell membrane. Here, we describe a novel pathway in mammalian cells whereby a hypotonic stimulus directly induces intracellular calcium elevations through transient receptor potential channels, which trigger AQP1 translocation. This translocation, which has a direct role in cell volume regulation, occurs within 30 s and is dependent on calmodulin activation and phosphorylation of AQP1 at two threonine residues by protein kinase C. This direct mechanism provides a rationale for the changes in water transport that are required in response to constantly changing local cellular water availability. Moreover, because calcium is a pluripotent and ubiquitous second messenger in biological systems, the discovery of its role in the regulation of AQP translocation has ramifications for diverse physiological and pathophysiological processes, as well as providing an explanation for the rapid regulation of water flow that is necessary for cell homeostasis.

Background: Emerging evidence supports the view that (AQP) aquaporin water channels are regulators of transcellular\ud water flow. Consistentwith their expression in most tissues, AQPs are associatedwith diverse physiological\ud and pathophysiological processes.\ud Scope of review: AQP knockout studies suggest that the regulatory role of AQPs, rather than their action as passive\ud channels, is their critical function. Transport through all AQPs occurs by a common passive mechanism, but their\ud regulation and cellular distribution varies significantly depending on cell and tissue type; the role of AQPs in cell\ud volumeregulation (CVR) is particularly notable. This reviewexamines the regulatory role of AQPs in transcellular\ud water flow, especially in CVR.We focus on key systems of the human body, encompassing processes as diverse as\ud urine concentration in the kidney to clearance of brain oedema.\ud Major conclusions: AQPs are crucial for the regulation of water homeostasis, providing selective pores for the\ud rapidmovement ofwater across diverse cellmembranes and playing regulatory roles in CVR. Gatingmechanisms\ud have been proposed for human AQPs, but have only been reported for plant andmicrobial AQPs. Consequently, it\ud is likely that the distribution and abundance of AQPs in a particular membrane is the determinant of membrane\ud water permeability and a regulator of transcellular water flow.\ud General significance: Elucidating the mechanisms that regulate transcellular water flow will improve our understanding\ud of the human body in health and disease. The central role of specific AQPs in regulating water homeostasis\ud will provide routes to a range of novel therapies. This article is part of a Special Issue entitled Aquaporins.