The TASK-1 two-pore domain K+ channel is a molecular substrate for neuronal effects of inhalation anesthetics

Despite widespread use of volatile general anesthetics for well over a cent ury, the mechanisms by which they alter specific CNS functions remain uncle ar. Here, we present evidence implicating the two-pore domain, pH-sensitive TASK-1 channel as a target for specific, clinically important anesthetic e ffects in mammalian neurons. In rat somatic motoneurons and locus coeruleus cells, two populations of neurons that express TASK-1 mRNA, inhalation ane sthetics activated a neuronal K+ conductance, causing membrane hyperpolariz ation and suppressing action potential discharge. These membrane effects oc curred at clinically relevant anesthetic levels, with precisely the steep c oncentration dependence expected for anesthetic effects of these compounds. The native neuronal K+ current displayed voltage- and time-dependent prope rties that were identical to those mediated by the open-rectifier TASK-1 ch annel. Moreover, the neuronal K+ channel and heterologously expressed TASK- 1 were similarly modulated by extracellular pH. The decreased cellular exci tability associated with TASK-1 activation in these cell groups probably ac counts for specific CNS effects of anesthetics: in motoneurons, it likely c ontributes to anesthetic-induced immobilization, whereas in the locus coeru leus, it may support analgesic and hypnotic actions attributed to inhibitio n of those neurons.