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A large and diverse array of small hydrophobic molecules induce generalanesthesia. Their efficacy as anesthetics has been shown to correlate both withtheir affinity for a hydrophobic environment and with their potency ininhibiting certain ligand gated ion channels. Here we explore the effects thatn-alcohols and other liquid anesthetics have on the two-dimensional miscibilitycritical point observed in cell derived giant plasma membrane vesicles (GPMVs).We show that anesthetics depress the critical temperature (Tc) of these GPMVswithout strongly altering the ratio of the two liquid phases found below Tc.The magnitude of this affect is consistent across n-alcohols when theirconcentration is rescaled by the median anesthetic concentration (AC50) fortadpole anesthesia, but not when plotted against the overall concentration insolution. At AC50 we see a 4{\deg}C downward shift in Tc, much larger than istypically seen in the main chain transition at these anesthetic concentrations.GPMV miscibility critical temperatures are also lowered to a similar extent bypropofol, phenylethanol, and isopropanol when added at anestheticconcentrations, but not by tetradecanol or 2,6 diterbutylphenol, two structuralanalogs of general anesthetics that are hydrophobic but have no anestheticpotency. We propose that liquid general anesthetics provide an experimentaltool for lowering critical temperatures in plasma membranes of intact cells,which we predict will reduce lipid-mediated heterogeneity in a way that iscomplimentary to increasing or decreasing cholesterol. Also, several possibleimplications of our results are discussed in the context of current models ofanesthetic action on ligand gated ion channels.

Liquid general anesthetics lower critical temperatures in plasma membrane vesicles