K⁺-Cl^- Cotransport in Vertebrate Red Cells

Abstract

The “pump-leak” model of Tosteson and Hoffman (1960) presented an elegant and simple paradigm for regulation of red blood cell (RBC) cation content and volume. It emphasised the importance of a specific, ouabain-sensitive, Na⁺/K⁺ pump, driven by ATP, as the primary active transport process for maintaining high intracellular K⁺, balancing K⁺ loss through passive processes. The passive pathways were not defined. For many years, they were thought of as non-specific “leaks” by which ions could travel down their electrochemical gradients across the cell membrane. A second route for mediated Na⁺ efflux persisted, however, in cells treated with ouabain, and thereby lacking functional Na⁺/K⁺ pump activity (Hoffman and Kregenow 1966). In these ouabain-treated cells, movement of K⁺ ions was not proportional to the electrochemical gradient for K⁺ unless Cl^- was removed, implying coupled ion movements (Funder and Wieth 1967). The second Na⁺ “pump” was found to require an outward K⁺ gradient (Sachs 1971). It became apparent that Na⁺ and K⁺ fluxes were dependent on each other (Wiley and Cooper 1974), hence the notion of Na⁺-K⁺ cotransport. Subsequently, their Cl^--dependence raised the possibility of Na⁺-K⁺-Cl^- cotransport (Schmidt and McManus 1977; Dunham and Ellory 1980). Later a second passive pathway for K⁺ transport, requiring Cl^- but not Na⁺, was observed (Dunham and Ellory 1981).