THE MOLECULAR BASIS OF MEMBRANE EXCITABILITY

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Asymmetric currents attributed to the movement of the Na channel gates have been measured in various tissues. In frog skeletal muscle asymmetric currents, similar to those recorded from giant axons, has been measured in fibers with a wide range of limitation sodium conductances. Asymmetric charge is not proportional to limiting sodium conductance. Holding at -150 mV doubles the amount of charge moved when stepping to 0 mV, compared to holding at -90 mV. These two observations imply that some of the fast asymmetric current measure in frog muscle is not functional Na gating current. Two kinds of experiments will be performed in an effort to distinguish functional from non-functional gating current. First, the kinetics of the charge that becomes mobile at a holding potential of -150 mV will be compared with the kinetics of charge that is mobile at a holding potential of -90 mV. Second, aconitine will be used to modify kinetics of Na channels. By determining the portion of gating charge with modified kinetics it should be possible to separate functional gating charge from other asymmetric charge. Aconitine depresses peak sodium conductance. Single channel conductance will be measured in order to determine whether this depression is due to loss of channels or to decreased single channel conductance. The possibility that TTX protects against aconitine modification of sodium channels will also be investigated. The large variability is limiting Na conductances measured in frog twitch muscle is likely a consequence of species, seasonal or geographic variability in frogs. Efforts will be made to develop a mammalian muscle gating current preparation without these disadvantages.