The Na+/I- symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate
The Na+/I- symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate
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DOI：
10.1073/pnas.0707207104
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发表时间：
2007-12-18
影响因子：
11.1
通讯作者：
Carrasco, Nancy
中科院分区：
文献类型：
--
作者：
Dohan, Orsolya;Portulano, Carla;Carrasco, Nancy
Na+/I-同调体（NIS）是一种关键的质膜蛋白，在甲状腺、哺乳期乳房和其他电致化学计量为2 Na+/I-的组织中介导活跃的I-摄取。在甲状腺中，nis介导的I-摄取是含碘甲状腺激素生物合成的第一步，这对于生命早期中枢神经系统的正常发育至关重要。在哺乳期的乳房中，NIS介导I-向乳汁的转运，从而为哺乳中的新生儿提供这种必需的阴离子。高氯酸盐（ClO4-）是一种众所周知的竞争性NIS抑制剂。暴露于受ClO4-污染的食物和水在美国人口中很常见，这种暴露对公共健康的影响目前正在争论中。迄今为止，仍不确定ClO4-是NIS阻滞剂还是NIS的转运底物。在这里，我们证明了体外和体内NIS积极运输ClO4-，包括ClO4-转运到牛奶。一个简单的数学通量模型准确地预测了ClO4-输运对I-积累速率和程度的影响。引人注目的是，Na+/ClO4-转运化学计量是电中性的，这表明NIS转运不同的底物具有不同的化学计量。NIS积极地将ClO4-富集在母乳中，这表明新生儿暴露于高水平的ClO4-可能比之前认为的造成更大的健康风险，因为ClO4-因此会直接抑制新生儿甲状腺I-的摄取。
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 (ClO4-) is a well known competitive inhibitor of NIS. Exposure to food and water contaminated with ClO4- 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 ClO4- is a NIS blocker or a transported substrate of NIS. Here 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. Strikingly, the Na+/ClO4- transport stoichiometry is electroneutral, uncovering that NIS translocates different substrates with different stoichiometries. That NIS actively concentrates ClO4- in maternal milk suggests that exposure of newborns to high levels of ClO4- may pose a greater health risk than previously acknowledged because ClO4- would thus directly inhibit the newborns' thyroidal I- uptake.