Allosteric regulation of mammalian Na/I symporter activity by perchlorate.

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:1ClO), 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 ClO transport is due to ClO binding to a high-affinity non-transport allosteric site that prevents Na from binding to one of its two sites. Furthermore, low concentrations of ClO 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 ClO pollution in drinking water is more dangerous than previously thought.