TASK-1 tandem pore potassium (K₂P) channels have been found to be activated by volatile anesthetics and thereby decrease cellular input resistance and excitability during general anesthesia. Here, we describe that at higher doses of volatile anesthetics a functionally distinct mechanism of action prevails that results in a decrease of channel activity and may contribute to cellular hyperexcitability. Halothane was found to induce a dose-dependent increase of TASK-1 channel activity with an EC₅₀ of 0.33 mM. When the halothane concentration is raised >1 mM, however, the initial activation overlaps with a profound inhibition of TASK-1 currents (but not TASK-3 currents) with an IC₅₀ of 2.2 mM. As suggested by Talley & Bayliss (2001) a cytoplasmic stretch of six amino acids close to the fourth transmembrane region of the TASK-1 subunit may be important for channel gating. When we removed this motif halothane-induced channel activation was completely abolished, but channel inactivation at higher concentrations remained unaltered. Conversely, a COOH-terminal deletion mutant downstream of the six-amino acid motif displayed loss of halothane-induced inactivation, whereas channel activation at lower concentrations was unaffected. Our results demonstrate that different structural domains in TASK channels mediate functionally inverse responses to volatile anesthetics and thus may account for clinical side effects in the use of these substances.