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

DOHAN, O; PORTULANO, C; BASQUIN, C; PARODER, M; NICOLA, JP; MAESTRAS, M; REYNA-NEYRA, A; AMZEL, LM; CARRASCO, N

Berlin

Congreso; European Congress of Endocrinology; 2008

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 invitro  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.