On the electrogenic sodium pump in mammalian non‐myelinated nerve fibres and its activation by various external cations

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Abstract
The hyperpolarization that follows a period of electrical activity (the post-tetanic hyperpolarization) in mammalian non-myelinated nerve fibers was studied. Under certain circumstances this post-tetanic hyperpolarization is a result of activity of an electrogenic Na pump that normally is absolutely dependent on the external presence of K. When the external chloride is replaced by sulphate or by isethio-nate the post-tetanic hyperpolarization, which in normal Locke solution is only a few millivolts in amplitude, is increased usually to about 20 mV, and on occasion to 35 mV. This effect of removing the chloride takes several minutes to develop and is consistent with the idea that the increase in the post-tetanic response is the result of removing the short-circuiting effect of internal chloride ions (by their being washed out into the chloride-free bathing medium). Small anions, such as chloride, nitrate, iodide, bromide, and thiocyanate can short-circuit the electrogenic pump, whereas larger anions such as sulphate and isethionate cannot. The bicarbonate ion, which is larger than chloride, short-circuits the pump but less effectively. In Locke solution containing 5 mM potassium the post-tetanic hyperpolarization declines exponentially, with a time constant of about 1-3 min. The time constant is inversely related to the external K concentration. However, when the external K concentration is zero the hyperpolarization declines rapidly to a very small value. Subsequent addition of K to the bathing medium causes a marked redevelopment of the hyperpolarization. This K-activated response declines exponentially with a time constant that is inversely related to the K concentration. When the added Kconcentration is 5 mM, the time constant is 1.9 min. The amplitude of the K-activated response increases with increasing concentrations of K. Other cations can produce this activated response. Thus, Tl is more effective than, Rb as effective as, Cs and ammonium about 1/10 as effective as, and Li ions about 1B0 as effective as K in producing the activated response. Choline is quite ineffective. The size of the post-tetanic response is little affected by changes in the duration of the period of stimulation. However, increasing the duration definitely increases the time constant of recovery. Reducing the external Na concentration increases the size of the post-tetanic hyperpolarization (by about 25%), but the effect is complex and requires further study. Reducing the Ca on the Locke-solution from 2.2 to 0.2 mM has no appreciable effect on the post-tetanic response, nor has increasing the pH of the Locke from 7.2 to 9.2. When the membrane potential is increased or decreased, by externally applied currents, there is relatively little change in the post-tetanic response. A mathematical model of the electrogenic pump, devised to mimic the experimental results, was analysed with an analogue computer. A satisfactory agreement between model and experiment was achieved by a model in which: the rate of extrusion of Na ions depends on the degree to which a pool of carrier molecules on the inside surface of the membrane is combined with Na; each carrier molecule transfers three Na ions at a time; the constant for extrusion of Na ions also depends on the presence externally of K ions, which combine with some sites on the external surface of the membrane that are half-saturated when the external concentration of K is 2.8 mM.