title: Kinetic evidence that the Na-PO4 cotransporter is the molecular mechanism for Na/Li exchange in human red blood cells.
abstract: 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 Ki, 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 Liout/Nain exchange when Liout 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.
authors.affiliation: Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Sammy
authors.initials: S
authors.lastname: Elmariah
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gunn
mesh_terms: D001149:Arsenates / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D020134:Catalytic Domain / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008094:Lithium / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D010710:Phosphates / Q000378:metabolism / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism* / Q000494:pharmacology; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D027981:Symporters / Q000187:drug effects / Q000378:metabolism*
chemical_list: D001149:Arsenates; D010710:Phosphates; C493553:SLC17A4 protein, human; D050608:Sodium-Phosphate Cotransporter Proteins; D050609:Sodium-Phosphate Cotransporter Proteins, Type I; D027981:Symporters; D008094:Lithium; D012964:Sodium; C025657:arsenic acid