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+: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. Transport and electrophysiology measurements of the Na+/I− symporter reveal that environmental pollutant perchlorate binds to an allosteric site and inhibits I− transport not only by competition but also by changing the stoichiometry of I− transport.