Lithium efflux through the Na/K pump in human erythrocytes

Abstract

ABSTRACIActive Li efflux from human erythrocytes was shown to be mediated by the Na/K pump: (i) intracellular Li (Li,) 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, Lic 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 Lic 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. Active influx of Li into human erythrocytes was first reported in 1957 (1). This influx is probably mediated by the Na/K pump because extracellular Li promotes active Na efflux (2-4) and also promotes active K influx at very low external K concentrations (5). The chemical similarity between Li and Na prompted attempts to demonstrate Li efflux through the Na/K pump; the results of all these attempts in erythrocytes were negative (2,3,6).These studies are of additional interest in light of the therapeutic effect of Li salts in patients with manic depressive illness (7,8) and the apparent higher ratio of intracellular Li to plasma Li concentrations in patients who respond to Li treatment than in nonresponders (9, 10) (nonresponders include both healthy individuals and affected patients not responding to treatment); however, there is evidence to the contrary (11). During Li treatment, the steady-state Li concentration in vivo normally is lower in the erythrocytes than in the plasma, suggestingactive Li efflux, but this gradient has been ascribed to a Na/Li counter transport system that is independent of the Na/K pump (12, 13) and the Na/Na exchange mediated by it (14).In the attempts to show pump-mediated Li efflux from erythrocytes, there were substantial intracellular Na or K concentrations (2, 3, 6), which probably inhibited any association of Li with Na translocation sites on the pumps. Whittam and Ager (15) presented evidence that, in resealed erythrocyte ghosts, Li promoted ouabain-sensitive ATPase acti...

Interaction of external alkali metal ions with the Na-K pump of human erythrocytes: a comparison of their effects on activation of the pump and on the rate of ouabain binding.

“…Lithium can act both as an analog for K at the external aspect of the pump (Sachs and Welt, 1967;Beaug6 and del Campillo, 1976) and as an analog for Na intracellularly (Dunham and Senyk, 1977). We find that Li in Na-free solutions behaved similarly to Cs in that it stimulated both the pump and ouabain binding (Fig.…”

Lithium Causes G2 Arrest of Renal Principal Cells

“…6 Lithium mainly enters principal cells through the epithelial sodium channel at the apical surface 6,7 and, consequently, accumulates in principal cells due to the low affinity of the basolateral Na + efflux pump Na + /K + -ATPase for lithium. 6,8 How lithium downregulates AQP2 remains unclear but likely involves glycogen synthase kinase type 3b, which is of importance in AVP-regulated antidiuresis and is inhibited by lithium. [9][10][11] Lithium also affects AQP2-mediated water reabsorption by the elevated tubular release of prostaglandin E 2 .…”

5-(N,N-dimethyl)amiloride-sensitive Na-Li exchange in isolated specimens of human atrium.

“…Alternatively, the differences could be due to differences between delays in extracellular diffusion ofLi', a delay that for cat papillary muscle may be quite substantial during the first 30 min after the transfer (3). However, it does not seem plausible that delays in extracellular diffusion also accounts for 25 mmol Li'/liter intracellular water measured even 2 h after the transfer ofcat papillary muscles (3). Such findings suggests that not all intracellular Li' is freely exchangeable.…”

“…In contrast, outward transport of Li' by the Na, K-pump has been demonstrated in red blood cells, although under extreme experimental conditions (20,25). However, the selectivity of Na+ over LiW is so great that ouabain-sensitive LiW efflux is undetectable unless the intracellular Na+ concentration is less than 1 mM (23).…”

“…6 B) were due to competitive inhibition of cellular Na'-uptake by Lie, it should be possible to overcome the inhibition by increasing the Na' concentration in the rewarming solution containing 25 (Fig. 6 B) was overcome by increasing the Na' concentration from 25 to 106 mM.…”