TREK-1 is a member of the mammalian two P domain K+ channel family. Mouse TREK-1 activity, in transiently transfected COS cells, is reduced at negative resting membrane potentials by both an external Mg2+ block and an intrinsic voltage-dependent gating mechanism leading to a strong outward rectification. Deletional and chimeric analysis demonstrates that the carboxy terminal domain of TREK-1, but not the PKA phosphorylation site S333, is responsible for voltage-dependent gating. Since the same region is also critically required for TREK-1 mechano-gating, both mechanisms might be functionally linked. Preferential opening of TREK-1 at depolarized potentials will greatly affect action potential duration, recovery from inactivation and neuronal repetitive firing activity. (C) 2002 Elsevier Science (USA).