The Na+/I symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate.
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 CNS development. In the lactating breast, NIS mediates the translocation of I(-) to the milk, thus supplying this essential anion to the nursing newborn. Perchlorate (ClO(4)(-)) is a well known competitive inhibitor of NIS. Exposure to food and water contaminated with ClO(4)(-) is common in the U.S. population, and the public health impact of such exposure is currently being debated. To date, it is still uncertain whether ClO(4)(-) is a NIS blocker or a transported substrate of NIS. Here we show in vitro and in vivo that NIS actively transports ClO(4)(-), including ClO(4)(-) translocation to the milk. A simple mathematical fluxes model accurately predicts the effect of ClO(4)(-) transport on the rate and extent of I(-) accumulation. Strikingly, the Na(+)/ ClO(4)(-) transport stoichiometry is electroneutral, uncovering that NIS translocates different substrates with different stoichiometries. That NIS actively concentrates ClO(4)(-) in maternal milk suggests that exposure of newborns to high levels of ClO(4)(-) may pose a greater health risk than previously acknowledged because ClO(4)(-) would thus directly inhibit the newborns' thyroidal I(-) uptake.
Dohán
Orsolya
O
Departments of Molecular Pharmacology and Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Portulano
Carla
C
Basquin
Cécile
C
Reyna-Neyra
Andrea
A
Amzel
L Mario
LM
Carrasco
Nancy
N
D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D004285:Dogs; D004785:Environmental Pollutants / Q000378:metabolism*; D007455:Iodine / Q000032:analysis / Q000378:metabolism*; D007700:Kinetics; D008892:Milk / Q000737:chemistry; D008962:Models, Theoretical; D010472:Perchlorates / Q000032:analysis / Q000378:metabolism*; D051381:Rats; D027981:Symporters / Q000378:metabolism*; D014162:Transfection; D000099209:Sodium-Iodide Symporters
D004785:Environmental Pollutants; D007455:Iodine; D010472:Perchlorates; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C494474:perchlorate