This paper reports the presence of human red cells of an additional ouabain-insensitive transport pathway for lithium ions, the Li-K cotransport. Several kinds of observations support this conclusion. Cells loaded to contain only K, Na, or Li do not exhibit furosemide-sensitive efflux. Simultaneous presence of K and Li on the same side of the membrane mutually stimulates furosemide-sensitive Li and K fluxes from that side. Cells loaded with both Na and Li exhibit no furosemide-sensitive Li efflux. Thus, Li can apparently replace Na but not K on the outward Na-K cotransport system in human red cells. Furthermore, Lio, like Ko, inhibits outward Na-K cotransport. Additional proof for coupled Li-K cotransport is provided by the observation that an outwardly directed K electrochemical potential gradient can drive net outwardly directed K electrochemical potential gradient can drive net outward Li movement against its gradient. There are several differences between Li-K cotransport and Li-Na countertransport. The cotransport system has an apparent affinity for Li that is about one-half that for Na and 30 times lower than the counter-transport system. Furosemide and chloride replacement inhibit cotransport but do not affect countertransport. The PCMBS loading procedure irreversibly inhibits countertransport but not cotransport. Furthermore, the two systems can apparently function at maximal rates simultaneously. Present evidence, than, indicates that the two pathways can be separated operationally as two different systems.

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