Measurements of O₂ permeability in lipid bilayers have indicated that it is much lower than previously thought and, therefore, the existence of membrane O₂ channels has been suggested. We hypothesized that, besides its role as water channel, aquaporin-1 (AQP1) could also work as an O₂ channel, since this transmembrane protein appears to be CO₂ permeable and is highly expressed in cells with rapid CO₂ and O₂ turnover (erythrocytes and microvessel endothelium). In mammalian cells over-expressing AQP1 and exposed to hypoxia, the loss of cytosolic O₂, as well as stabilization of the O₂-dependent hypoxia-inducible transcription factor and expression of its target genes, are accelerated. In normoxic endothelial cells, knocking down AQP-1 produces induction of hypoxia-inducible genes. Moreover, lung AQP1 is markedly up-regulated in animals exposed to hypoxia. These data suggest that AQP1 could facilitate O₂ diffusion across the cell membrane. Moreover, the presence of AQP1 in the rat neonatal adrenal medulla and type I cells of rat carotid body has been also confirmed. The expression pattern of AQP1 in these tissues fit with their CO₂ and O₂ sensitivity. The novel proposed function of AQP1 as a facilitative transmembrane O₂ pathway together with its known CO₂ permeability would make of this protein a key element in the sensory transduction process increasing the sensitivity to gases of chemoresponsive cells.