Physiological sodium concentrations enhance the iodide affinity of the Na(+)/I(−) symporter

The Na(+)/I(−) symporter (NIS) mediates active I(−) transport--the first step in thyroid hormonogenesis-- with a 2Na(+):1I(−) stoichiometry. NIS-mediated (131)I(−) treatment of thyroid cancer post-thyroidectomy is the most effective targeted internal radiation cancer treatment available. Here, to uncover mechanistic information on NIS, we use statistical thermodynamics to obtain K(d)s and estimate the relative populations of the different NIS species during Na(+)/anion binding and transport. We show that, although the affinity of NIS for I(−) is low (K(d)=224μM), it increases when Na(+) is bound (K(d)=22.4μM). However, this K(d) is still much higher than the submicromolar physiological I(−) concentration. To overcome this, NIS takes advantage of the extracellular Na(+) concentration and the pronounced increase in its own affinity for I(−) and for the second Na(+) elicited by binding of the first. Thus, at physiological Na(+) concentrations, ~79% of NIS molecules are occupied by two Na(+) ions and ready to bind and transport I(−).