Hypoxic inhibition of background K+ channels is crucial to O-2 sensing by chemoreceptor tissues, but direct demonstration Of O-2 sensitivity by any member of this K+ channel family is lacking. HEK293 cells were transfected with a pcDNA3.1-hTASK1 construct; expression of hTASK1 was verified using RT-PCR and immunocytochemistry. Whole-cell K+ currents of cells stably expressing hTASK-1 were, as anticipated, extremely sensitive to extracellular pH, within the physiological range (IC50 approximate to 7.0). All cells expressing this signature pH sensitivity were acutely modulated by pO(2); reduction of pO(2) from 150 to < 40 mmHg (at pH 7.4) caused rapid and reversible suppression of pH-sensitive K+ currents. Furthermore, these two regulatory signals clearly acted at the same channel, since the magnitude of the O-2-sensitive current was dependent on the extracellular pH. These data represent the first direct verification that hTASK1 is O-2-sensitive and reinforce the idea that this K+ channel is key to O-2 sensing in chemoreceptors.