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SINCE the 1980s, molecular hypotheses attributing general anesthesia to nonspecific membrane biophysical perturbations have largely receded, while researchers have embraced the idea that anesthetic drugs act directly at protein targets, that is, classical receptors. However, there is little evidence supporting this hypothesis for volatile anesthetics. Pandit et al. in this volume of Anesthesiology add another piece to the challenging puzzle of volatile anesthetic mechanisms. The new work by Pandit et al. relates clinically to a toxic effect of volatile anesthetics: inhibition of the hypoxic ventilatory response. Loss of this important physiologic reflex may contribute to postoperative hypoventilation, hypoxia, and associated morbidity. In the neural circuits underlying the hypoxic ventilatory response, glomus type I cells located in the carotid bodies and aortic bodies are the sensory cells, and their molecular chemosensing elements include TWIKrelated acid-sensitive potassium channels (TASK; where TWIK is tandem pore-domain weakly inward-rectifying potassium-conductive), specifically heterodimers of TASK-1 and TASK-3 subunits. TASK channels are members of the two pore-domain potassium channel family and are partially active under normal physiologic conditions. They are directly inhibited by acute decreases in pH and indirectly by decreases in Po 2 , reducing potassium conductance and depolarizing glomus cells, leading to increased intracellular calcium, release of neurotransmitters, and ultimately stimulating both respiratory frequency and tidal volume. Pharmacologic TASK channel inhibitors, such as doxapram, also stimulate pulmonary ventilation. On the other hand, volatile anesthetics activate TASK channels, hyperpolarizing glomus cells and antagonizing the hypoxic ventilatory response. Volatile anesthetics also activate some other two pore-domain potassium channels, including TREK-1 (a TWIKrelated potassium channel), which contributes to hypnotic and neuroprotective effects. Pandit et al. studied the effects of halothane, isoflurane, and mixtures of these two volatile anesthetics, using calcium-sensitive dye fluorescence to track intracellular [Ca] in glomus cells and voltage-clamp electrophysiology to measure potassium currents conducted by native TASK 1/3 channels in glomus cells and TASK-1 homodimeric channels expressed in HEK293 (kidney) cells. Halothane and isoflurane produced concentration-dependent activation of TASK channels and inhibition of hypoxia-induced intracellular [Ca] signals. The effects of halothane were consistently much larger than those of isoflurane. When halothane was coapplied with isoflurane in these experiments, the effects were subadditive. Notably, when a fixed halothane concentration was coapplied with increasing isoflurane concentrations, effects were smaller than those of halothane alone, increasingly approaching those of isoflurane alone. Pandit et al. recognized that their results could reflect competitive interactions of two agonists, one high efficacy (halothane) and one low efficacy (isoflurane), both reversibly binding at a shared receptor site. Starting with halothane alone, as the coapplied concentration of isoflurane “The future of general anesthetic pharmacology, ideally characterized by low toxicity and favorable pharmacokinetics, depends on identifying key targets that enable precise pharmacologic manipulation.”