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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.