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.
03 - 07 May 2008
European Society of Endocrinology