3-Iodothyronamine (T 1AM) is a naturally occurring thyroid hormone metabolite with distinct biological effects that are opposite those of thyroid hormone. The known molecular targets of T 1AM include both plasma membrane and intracellular proteins, suggesting that intracellulartransport of T 1AM may be an important component of its action, although no uptake mechanism has yet been described. Using various human cell lines, we show that, indeed, cellular uptake of T 1AM occurs in multiple cell types and that this process involves specific, saturable, and inhibitable transport mechanisms. These mechanisms are sodium and chloride independent, pH dependent, thyronamine specific, and do not involve the likely candidate transporters of other monoamines, organic cations, or thyroid hormones. A large-scale RNA interference screen targeting the entire solute carriersuperfamily of transporter genes revealsthatthetransport of T 1AM into cells involves multiple transporters, and we identify eight transporters that may contribute to the uptake of T 1AM in HeLa cells. This type of transporter small interfering RNA screening approach can be used in general to identify the constellation of transporters that participate in the intracellular disposition of compounds.
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