ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2008) 16 S17.4

Novel insights on the Na+/I- symporter (NIS): it mediates electroneutral active transport of the environmental pollutant perchlorate

O Dohán1, C Portulano1, C Basquin1, M Paroder1, JP Nicola1, MJ Maestas3, S Eskandari3, A Reyna-Neyra2, LM Amzel4 & N Carrasco1

1Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA; 2Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, USA; 3Biological Sciences Department, California State Polytechnic University, Pomona, California, USA; 4Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.

The Na+/I symporter (NIS) is a key plasma membrane protein that mediates active I uptake in the thyroid, lactating breast, and other tissues with an electrogenic stoichiometry of 2 Na+ per I. In the thyroid, NIS-mediated I uptake is the first step in the biosynthesis of the iodine-containing thyroid hormones, which are essential early in life for proper development of the central nervous system. In the lactating breast, NIS mediates the translocation of I to the milk, thus supplying this essential anion to the nursing newborn. Perchlorate (ClO4) is a well-known competitive inhibitor of NIS. Exposure to food and water contaminated with ClO4 is common in the US population and the public health impact of such exposure is currently being intensely debated. Settling the controversy on whether ClO4 is a NIS blocker or a transported substrate of NIS, we show in vitro and in vivo that: NIS actively transports ClO4, including ClO4 translocation to the milk; a simple mathematical fluxes model accurately predicts the effect of ClO4 transport on the rate and extent of I accumulation; and, strikingly, the Na+/ClO4 transport stoichiometry is electroneutral, uncovering that NIS translocates different substrates with different stoichiometries, an unprecedented finding for any transporter. That NIS actively concentrates ClO4 in the maternal milk suggests that exposure of newborns to high levels of ClO4 may pose a greater health risk than previously acknowledged, as ClO4 would thus directly inhibit the newborns’ thyroidal I uptake. In addition, we have generated mutant NIS proteins that transport ClO4 electrogenically.