TASK-2 is a K_2P K⁺ channel considered as a candidate to mediate CO₂ sensing in central chemosensory neurons in mouse. Neuroepithelial cells in zebrafish gills sense CO₂ levels through an unidentified K_2P K⁺ channel. We have now obtained zfTASK-2 from zebrafish gill tissue that is 49 % identical to mTASK-2. Like its mouse equivalent, it is gated both by extra- and intracellular pH being activated by alkalinization and inhibited by acidification. The pH_i dependence of zfTASK-2 is similar to that of mTASK-2, with pK _1/2 values of 7.9 and 8.0, respectively, but pH_o dependence occurs with a pK _1/2 of 8.8 (8.0 for mTASK-2) in line with the relatively alkaline plasma pH found in fish. Increasing CO₂ led to a rapid, concentration-dependent (IC₅₀ ~1.5 % CO₂) inhibition of mouse and zfTASK-2 that could be resolved into an inhibition by intracellular acidification and a CO₂ effect independent of pH_i change. Indeed a CO₂ effect persisted despite using strongly buffered intracellular solutions abolishing any change in pH_i, was present in TASK-2-K245A mutant insensitive to pH_i, and also under carbonic anhydrase inhibition. The mechanism by which TASK-2 senses CO₂ is unknown but requires the presence of the 245–273 stretch of amino acids in the C terminus that comprises numerous basic amino acids and is important in TASK-2 G protein subunit binding and regulation of the channel. The described CO₂ effect might be of importance in the eventual roles played by TASK-2 in chemoreception in mouse and zebrafish.