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^-.