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The effects of external Rb+ on the efflux of 42K+ from whole frog sartorius muscles loaded with 305 mM K+ and 120 mM Cl- were studied. K+ efflux is activated by [Rb+]o less than about 40 mM according to a sigmoid relation similar to that for activation by [K+]o. At [Rb+]o greater than 40 mM, K+ efflux declines, although at [Rb+]o = 300 mM it is still greater than at [Rb+]o = 0 mM. For low concentrations, the increment in K+ efflux over that in K+-and Rb+-free solution, delta K, is described by the relation delta k = a[X+]on, for both K+ and Rb+. The value of a is larger for Rb+ than for K+, while the values of n are similar; the activation produced by a given [Rb+]o is larger than that by an equal [K+]o for concentrations less than about 40 mM. Adding a small amount of Rb+ to a K+-containing solution has effects on K+ efflux which depend on [K+]o. At low [K+]o, adding Rb+ increases K+ efflux, the effect being greatest near [K+]o = 30 mM and declining at higher [K+]o; at [K+]o above 40 mM, addition of Rb+ decreases K+ efflux. At [K+]o above 75 mM, where K+ efflux is largely activated, Rb+ reduces K+ efflux by a factor b, described by the relation b = 1/(1+c[Rb+]o). Activation is discussed in terms of binding to at least two sites in the membrane, and the reduction in K+ efflux by Rb+ at high [K+]o in terms of association with an additional inhibitory site.

Small bundles of frog skeletal muscle fibers were loaded with 305 mM K+ and 120 mM Cl-, and 42K+ tracer efflux and influx were measured as a function of external K+ concentration ([K+]o) at a resting potential of -2 mV. As [K+]o was lowered from 305 mM, efflux decreased along a markedly sigmoidal curve, reaching a constant nonzero value at low [K+]o. Influx varied linearly with [K+]o at low [K+]o and more steeply at higher [K+]o. The ratio of influx to efflux was described by the equation: influx/efflux = exp[-n(V - VK)F/RT] with n = 2 at high [K+]o, but the ratio approached this equation with n = 1 at low [K+]o. Efflux did not depend on [K+]o when the membrane potential was raised to +36 mV, whereas at low [K+]o decreasing the membrane potential to -19 mV further activated the efflux. The results are discussed in terms of an inwardly rectifying potassium channel with two or more activating sites within the membrane that bind K+ and are accessible from the external solution.

ACTIVE LI EFFLUX FROM HUMAN ERYTHROCYTES WAS SHOWN TO BE MEDIATED BY THE NA/K PUMP: (i) intracellular Li (Li(c)) activated ouabain-sensitive K influx, and (ii) a portion of the Li efflux required external K and was inhibited by ouabain. In activating K influx, Li(c) interacts with the pump like Na rather than like K-depleting the cells of orthophosphate inhibited activation of K influx by intracellular K (K/K exchange) but did not inhibit Li-activated K influx. (To show these interactions of Li(c) with the Na/K pump, p-chloromercuribenzenesulfonate or nystatin was used to allow replacement of intracellular Na and K with Li and choline.) From kinetic studies of the pump, it was shown that the apparent affinity of the intracellular aspect of the Na/K pump for Li was an order of magnitude less than that for Na. From simultaneous measurements of ouabain-sensitive net fluxes of Li and K in Na-free cells, it was shown that the pump-mediated K influx and Li efflux were coupled. The stoichiometry of the coupling ratio was close to 1:1 for Li:K, different from the coupling ratio of 3:2 for Na:K in the pump's normal mode of operation. It had been shown previously that the Na/K pump in human erythrocytes mediates active Li influx. Because it also mediates active Li efflux, the molecular mechanisms for distinguishing between Na and K must be qualitatively different at the internal and external aspects of the pump. The possible relevance of the results of this study to manic depressive illness and Li therapy is discussed.

Frog skeletal muscle has a K+ channel called the inward rectifier, which passes inward current more readily than outward current. Gay and Stanfield (1977) described a voltage-dependent block of inward K+ currents through the inward rectifier by external Cs+ in frog muscle. Here, frog single muscle fibers were voltage clamped using the vaseline-gap voltage-clamp technique to study the effect of external [K+] on the voltage-dependent block of inward K+ currents through the inward rectifier by external Cs+. The block of inward K+ currents through the channel by external Cs+ was found to depend on external [K+], such that increasing the external concentration of the permeant ion K+ potentiated the block produced by the impermeant external Cs+. These findings are not consistent with a one-ion channel model for the inward rectifier. The Eyring rate theory formalism for channels, viewed as single-file multi-ion pores (Hille and Schwarz, 1978), was used to develop a two-site multi-ion model for the inward rectifier. This model successfully reproduced the experimentally observed potentiation of the Cs+ block of the channel by external K+, thus lending further support to the view of the inward rectifier as a multi-ion channel.