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Physiological sodium concentrations enhance the iodide affinity of the Na+/I- symporter.

ABSTRACT: 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 Kds 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 (Kd=224??M), it increases when Na(+) is bound (Kd=22.4??M). However, this Kd 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(-).

SUBMITTER: Nicola JP

PROVIDER: S-EPMC4248369 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Physiological sodium concentrations enhance the iodide affinity of the Na+/I- symporter.

Nicola Juan P JP Carrasco Nancy N Amzel L Mario LM

Nature communications 20140603

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 Kds and estimate the relative populations of the different NIS species during Na(+)/anion binding and transport. We show ...[more]

PMID: 24888603

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Project description:Background: The ability of thyroid follicular epithelial cells to accumulate iodide via the sodium/iodide symporter (NIS) is exploited to successfully treat most thyroid cancers, although a subset of patients lose functional NIS activity and become unresponsive to radioiodide therapy, with poor clinical outcome. Our knowledge of NIS regulation remains limited, however. While numerous membrane proteins are functionally regulated via dimerization, there is little definitive evidence of NIS dimerization, and whether this might impact upon radioiodide uptake and treatment success is entirely unknown. We hypothesized that NIS dimerizes and that dimerization is a prerequisite for iodide uptake. Methods: Coimmunoprecipitation, proximity ligation, and Förster resonance energy transfer (FRET) assays were used to assess NIS:NIS interaction. To identify residues involved in dimerization, a homology model of NIS structure was built based on the crystal structure of the dimeric bacterial protein vSGLT. Results: Abundant cellular NIS dimerization was confirmed in vitro via three discrete methodologies. FRET and proximity ligation assays demonstrated that while NIS can exist as a dimer at the plasma membrane (PM), it is also apparent in other cellular compartments. Homology modeling revealed one key potential site of dimeric interaction, with six residues <3Å apart. In particular, NIS residues Y242, T243, and Q471 were identified as critical to dimerization. Individual mutation of residues Y242 and T243 rendered NIS nonfunctional, while abrogation of Q471 did not impact radioiodide uptake. FRET data show that the putative dimerization interface can tolerate the loss of one, but not two, of these three clustered residues. Conclusions: We show for the first time that NIS dimerizes in vitro, and we identify the key residues via which this happens. We hypothesize that dimerization of NIS is critical to its trafficking to the PM and may therefore represent a new mechanism that would need to be considered in overcoming therapeutic failure in patients with thyroid cancer.

Dataset Information

Physiological sodium concentrations enhance the iodide affinity of the Na+/I- symporter.

Publications

Physiological sodium concentrations enhance the iodide affinity of the Na+/I- symporter.

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