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

• Published in: American Journal of Physiology: Cell Physiology 2003-08, Vol.285 (2), p.C446-C456
• Main Authors: Elmariah, Sammy, Gunn, Robert B
• Format: Article
• Language: English
• Subjects: Arsenates - pharmacology; Binding Sites - drug effects; Binding Sites - physiology; Catalytic Domain - drug effects; Catalytic Domain - physiology; Cell Membrane - drug effects; Cell Membrane - metabolism; Dose-Response Relationship, Drug; Erythrocytes - drug effects; Erythrocytes - metabolism; Extracellular Space - drug effects; Extracellular Space - metabolism; Humans; Intracellular Fluid - drug effects; Intracellular Fluid - metabolism; Kinetics; Lithium - metabolism; Lithium - pharmacology; Male; Models, Biological; Phosphates - metabolism; Phosphates - pharmacology; Sodium - metabolism; Sodium - pharmacology; Sodium-Phosphate Cotransporter Proteins; Sodium-Phosphate Cotransporter Proteins, Type I; Symporters - drug effects; Symporters - metabolism
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00606.2002

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 PO 4 transport that behaves as if it is mediated by the Na-PO 4 cotransporter (hBNP1) and provide evidence that this Na/Li-PO 4 cotransporter is also the mechanism for Na/Li exchange. First, external Li (>20 mM) activated PO 4 influx severalfold. Li activation of PO 4 influx was potentiated by the presence of external Na. Second, the ouabain-insensitive 22 Na efflux was stimulated by external Li and then inhibited by external PO 4 . Third, phloretin inhibited Na- and Li-activated PO 4 flux with the same K i , 0.25 mM. Fourth, external PO 4 (0.1–1.0 mM) inhibited ouabain-insensitive Li efflux only if external Na was present. Fifth, arsenate, a phosphate congener, inhibited both Na-PO 4 cotransport and Li-activated PO 4 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 PO 4 cotransporter and that Na/Li exchange behaves as if it is mediated by this Na/Li-PO 4 cotransporter when only one cation is bound. Plasma and intracellular PO 4 concentrations may be important regulators of Li transport and its therapeutic effects. sodium/lithium exchange; sodium,lithium-phosphate cotransport; human erythrocytes; kinetic model Address for reprint requests and other correspondence: R. B. Gunn, Emory Univ. School of Medicine, Dept. of Physiology, 615 Michael St.,Suite 601, Atlanta, GA 30322 (E-mail: rbgunn{at}emory.edu ).