Oxygen-sensitive K+ channels are important elements in the cellular response to hypoxia. Although much progress has been made in identifying their molecular composition, the structural components associated to their O-2-sensitivity are not yet understood. Recombinant Kv1.2 currents expressed in Xenopus oocytes are inhibited by a decrease in O-2 availability. On the contrary, heterologous Kv2.1 channels are O-2-insensitive. To elucidate the protein segment responsible for the O-2-sensitivity of Kv1.2 channels, we analyzed the response to anoxia of Kv1.2/Kv2.1 chimeric channels. Expression of chimeric Kv2.1 channels each containing the S4, the S1-S3 or the S6-COOH segments of Kv1.2 polypeptide resulted in a K+ current insensitive to anoxia. In contrast, transferring the S5-S6 segment of Kv1.2 into Kv2.1 produced an O-2-sensitive K+ current. Finally, mutating a redox-sensitive methionine residue (M380) of Kv1.2 polypeptide did not affect 02-SCnsitivity. Thus, the pore and its surrounding regions of Kv1.2 polypeptide confer its hypoxic inhibition. This response is independent on the redox modulation of methionine residues in this protein segment. (C) 2003 Elsevier Science (USA). All rights reserved.