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Aquaporin-3 mediates hydrogen peroxide uptake to regulate downstream intracellular signaling

Miller, Evan W., Dickinson, Bryan C., Chang, Christopher J.
Proceedings of the National Academy of Sciences of the United States of America 2010 v.107 no.36 pp. 15681-15686
NAD(P)H oxidase (H2O2-forming), NADP (coenzyme), aquaporins, fluorescence, hydrogen peroxide, image analysis, mammals, oxidative stress, toxicity
Hydrogen peroxide (H₂O₂) produced by cell-surface NADPH Oxidase (Nox) enzymes is emerging as an important signaling molecule for growth, differentiation, and migration processes. However, how cells spatially regulate H₂O₂ to achieve physiological redox signaling over nonspecific oxidative stress pathways is insufficiently understood. Here we report that the water channel Aquaporin-3 (AQP3) can facilitate the uptake of H₂O₂ into mammalian cells and mediate downstream intracellular signaling. Molecular imaging with Peroxy Yellow 1 Methyl-Ester (PY1-ME), a new chemoselective fluorescent indicator for H₂O₂, directly demonstrates that aquaporin isoforms AQP3 and AQP8, but not AQP1, can promote uptake of H₂O₂ specifically through membranes in mammalian cells. Moreover, we show that intracellular H₂O₂ accumulation can be modulated up or down based on endogenous AQP3 expression, which in turn can influence downstream cell signaling cascades. Finally, we establish that AQP3 is required for Nox-derived H₂O₂ signaling upon growth factor stimulation. Taken together, our findings demonstrate that the downstream intracellular effects of H₂O₂ can be regulated across biological barriers, a discovery that has broad implications for the controlled use of this potentially toxic small molecule for beneficial physiological functions.