Abstract
Aquaporin-5 (AQP5) is a membrane water channel widely distributed in human tissues that was found up-regulated in different tumors and considered implicated in carcinogenesis in different organs and systems. Despite its wide distribution pattern and physiological importance, AQP5 short-term regulation was not reported and mechanisms underlying its involvement in cancer are not well defined. In this work, we expressed rat AQP5 in yeast and investigated mechanisms of gating, as well as AQP5’s ability to facilitate H2O2 plasma membrane diffusion. We found that AQP5 can be gated by extracellular pH in a phosphorylation-dependent manner, with higher activity at physiological pH 7.4. Moreover, similar to other mammalian AQPs, AQP5 is able to increase extracellular H2O2 influx and to affect oxidative cell response with dual effects: whereas in acute oxidative stress conditions AQP5 induces an initial higher sensitivity, in chronic stress AQP5 expressing cells show improved cell survival and resistance. Our findings support the involvement of AQP5 in oxidative stress and suggest AQP5 modulation by phosphorylation as a novel tool for therapeutics.
Highlights
Aquaporins (AQPs) are a family of highly conserved transmembrane channels that transport water and, in some cases, small solutes such as glycerol, driven by osmotic or solute gradients [1,2]
In addition to AQP5 interaction with oncogenes, its function as a water channel was proposed to be involved in cell migration, since AQP5 expression may facilitate changes in cell volume and shape that are crucial for migration [11]
The present study provides experimental evidences for the direct regulation of AQP5 water permeability by pH dependent on phosphorylation and for AQP5 involvement in cell oxidative stress response
Summary
Aquaporins (AQPs) are a family of highly conserved transmembrane channels that transport water and, in some cases, small solutes such as glycerol, driven by osmotic or solute gradients [1,2]. The 13 known mammalian isoforms (AQP0–12) are differentially expressed in several tissues/organs and show different permeability, structural features, and cellular localization. These proteins are involved in many biological functions including transepithelial fluid transport, brain edema, neuroexcitation, cell migration, adhesion, proliferation, differentiation, and metabolism [3,4]. Their numerous roles in physiology make these proteins essential for health, suggesting that modulation of AQP’s function or expression could have therapeutic potential in edema, cancer, obesity, brain injury, glaucoma, and several other conditions [5]. In addition to AQP5 interaction with oncogenes, its function as a water channel was proposed to be involved in cell migration, since AQP5 expression may facilitate changes in cell volume and shape that are crucial for migration [11]
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