UC Irvine

The Na⁺/I^- symporter (NIS), the plasma membrane protein that actively transports I^- (stoichiometry 2Na⁺:1I^-) in thyroid physiology and radioiodide-based thyroid cancer treatment, also transports the environmental pollutant perchlorate (stoichiometry 1Na⁺:1ClO₄^-), which competes with I^- for transport. Until now, the mechanism by which NIS transports different anion substrates with different stoichiometries has remained unelucidated. We carried out transport measurements and analyzed these using a statistical thermodynamics-based equation and electrophysiological experiments to show that the different stoichiometry of ClO₄^- transport is due to ClO₄^- binding to a high-affinity non-transport allosteric site that prevents Na⁺ from binding to one of its two sites. Furthermore, low concentrations of ClO₄^- inhibit I^- transport not only by competition but also, critically, by changing the stoichiometry of I^- transport to 1:1, which greatly reduces the driving force. The data reveal that ClO₄^- pollution in drinking water is more dangerous than previously thought.