Rat Aquaporin-5 Is pH-Gated Induced by Phosphorylation and Is Implicated in Oxidative Stress

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.

Differential expression of aquaporin‐3 and aquaporin‐5 in pancreatic ductal adenocarcinoma

“…Regarding AQP3, its ability to transport glycerol that can be used for lipid biosynthesis and for ATP production may be advantageous for cell proliferation and migration in poorly differentiated tumors. In addition to water and glycerol, AQP3 and AQP5 also facilitate H 2 O 2 permeation that may be required for activation of the EGFR‐mediated cell signaling cascade in cancer cells . Our findings indicate that AQP5 overexpression is an early event in PDA progression and is independent of AQP3 overexpression since no statistically significant correlation was found between the expression of these two AQPs isoforms.…”

“…It is known that glycerol transported by AQP3 is necessary for lipid biosynthesis and can be metabolized to generate ATP, which is essential for cell division and migration . In addition, AQP3 and possibly AQP5 are also capable of transporting extracellular hydrogen peroxide (H 2 O 2 ), a reactive oxygen species that acts as a signaling molecule in signal transduction and may promote many aspects of tumor progression . Phosphorylation of AQP5, in turn, activates the RAS/MAPK pathway involved in cell proliferation and survival and this isoform may facilitate cancer cell motility due to its preferential polarization in the leading edge of migrating cells and by facilitating lamellipodium formation .…”

Gating in plant plasma membrane aquaporins: the involvement of leucine in the formation of a pore constriction in the closed state

“…The triggering events that promote the open-closed transition in PIP channels can be a drop in cytoplasmic pH, an increase in Ca 2+ concentrations or the dephosphorylation of specific serine residues [17][18][19][20][21][22]. Permeability regulation by pH has been reported for different aquaporins such as mammalian AQP3, AQP4, AQP5, AQP7 and plant AtTIP2;1, VvTIP2;1 among others [23][24][25][26][27][28]. But in particular, cytosolic acidification is a well-studied trigger for PIP channels gating as pH regulation of water transport has been described in red beet, Arabidopsis thaliana, strawberry, grape, and tobacco PIP aquaporins [17,20,[29][30][31][32][33].…”

Aquaporin-3 Attenuates Oxidative Stress-Induced Nucleus Pulposus Cell Apoptosis Through Regulating the P38 MAPK Pathway

“…Cellular Physiology and Biochemistry elimination of intracellular ROS-like substrates [36,37]. In this study, we used H 2 O 2 to induce an oxidative damage.…”