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Identification and Characterization of 3-Iodothyronamine Intracellular Transport

Departments of Biochemistry and Biophysics (A.G.I.) and Biopharmaceutical Sciences (K.M.G.), University of California, San Francisco, San Francisco, California 94143; and Department of Physiology and Pharmacology (T.S.S.), Oregon Health and Science University, Portland, Oregon 97239

Address all correspondence and requests for reprints to: Thomas S. Scanlan, Ph.D., Department of Physiology and Pharmacology, Oregon Health and Science University, Biomedical Sciences Building, Room 615, 3181 Southwest Sam Jackson Park Road, L334, Portland, Oregon 97239. E-mail: scanlant{at}ohsu.edu.

3-Iodothyronamine (T₁AM) is a naturally occurring thyroid hormone metabolite with distinct biological effects that are opposite those of thyroid hormone. The known molecular targets of T₁AM include both plasma membrane and intracellular proteins, suggesting that intracellular transport of T₁AM 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 T₁AM 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 carrier superfamily of transporter genes reveals that the transport of T₁AM into cells involves multiple transporters, and we identify eight transporters that may contribute to the uptake of T₁AM 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.