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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Kinetic evidence that the Na-PO₄ cotransporter is the molecular mechanism for Na/Li exchange in human red blood cells

Emory University School of Medicine, Atlanta, Georgia 30322-3110

Submitted 31 December 2002 ; accepted in final form 27 March 2003

The molecular basis for Na/Li exchange is unknown. Li can be transported by the Na pump, anion exchanger (AE1), a background leak, and the Na/Li exchanger. In vivo the intraerythrocyte concentration of Li results from the balance of passive entry, mostly on AE1, and the active extrusion on the Na/Li exchanger. Here we show that erythrocytes have Li-activated PO₄ transport that behaves as if it is mediated by the Na-PO₄ cotransporter (hBNP1) and provide evidence that this Na/Li-PO₄ cotransporter is also the mechanism for Na/Li exchange. First, external Li (>20 mM) activated PO₄ influx severalfold. Li activation of PO₄ influx was potentiated by the presence of external Na. Second, the ouabain-insensitive ²²Na efflux was stimulated by external Li and then inhibited by external PO₄. Third, phloretin inhibited Na- and Li-activated PO₄ flux with the same K_i, 0.25 mM. Fourth, external PO₄ (0.1–1.0 mM) inhibited ouabain-insensitive Li efflux only if external Na was present. Fifth, arsenate, a phosphate congener, inhibited both Na-PO₄ cotransport and Li-activated PO₄ flux with similar kinetics when Na or Li concentration was high but did not inhibit Li_out/Na_in exchange when Li_out concentration was low. The collective results suggest that both Na and Li are substrates for at least two sites on the same PO₄ cotransporter and that Na/Li exchange behaves as if it is mediated by this Na/Li-PO₄ cotransporter when only one cation is bound. Plasma and intracellular PO₄ concentrations may be important regulators of Li transport and its therapeutic effects.

sodium/lithium exchange; sodium,lithium-phosphate cotransport; human erythrocytes; kinetic model

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