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3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone

Abstract

Thyroxine (T4) is the predominant form of thyroid hormone (TH). Hyperthyroidism, a condition associated with excess TH, is characterized by increases in metabolic rate, core body temperature and cardiac performance. In target tissues, T4 is enzymatically deiodinated to 3,5,3′-triiodothyronine (T3), a high-affinity ligand for the nuclear TH receptors TRα and TRβ, whose activation controls normal vertebrate development and physiology1. T3-modulated transcription of target genes via activation of TRα and TRβ is a slow process, the effects of which manifest over hours and days. Although rapidly occurring effects of TH have been documented, the molecules that mediate these non-genomic effects remain obscure2,3. Here we report the discovery of 3-iodothyronamine (T1AM), a naturally occurring derivative of TH that in vitro is a potent agonist of the G protein–coupled trace amine receptor TAR1. Administering T1AM in vivo induces profound hypothermia and bradycardia within minutes. T1AM treatment also rapidly reduces cardiac output in an ex vivo working heart preparation. These results suggest the existence of a new signaling pathway, stimulation of which leads to rapid physiological and behavioral consequences that are opposite those associated with excess TH.

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Figure 1: TAR1 activation and tissue identification of 3-iodothyronamine.
Figure 2: Effect of thyronamines on rectal temperature of mice.
Figure 3: Cardiac effects of thyronamines.

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Acknowledgements

We thank S. Arttamangkul, A. Carlsson, L. Davis, D. Dawson, K. Garlid, G. Giraud, B. Habecker, S. Hillman, R. Hohimer, M.J. Kelly, L. Lester, G. Murdoch, P. Paucek, J.B. Roulet, L. Simon, M. Sonders, K. Thornburg and W. Woodward for discussions, encouragement and insight; A. Younkin, S. Forrester, L. Jurvic, Z. Rahman, Q. Yue and H. Xue for technical assistance; and M. von Zastrow for the hβ2AR HEK-293 cell line. This work was supported by the Oregon Health and Sciences University (OHSU) Heart Research Center, and by grants from the National Institute on Alchohol Abuse and Alcoholism (NIAAA) and National Institute on Drug Abuse (NIDA) (DA07262 to P.J.K.), the NIDA (DA107803 to D.K.G.), the Ministero dell'Istruzione dell'Università e della Ricerca (MIUR) (to R.Z.), the NIH (DK-52798 to T.S.S.) and the Sandler Family Supporting Foundation (to T.S.S.).

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Correspondence to Thomas S Scanlan or David K Grandy.

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Scanlan, T., Suchland, K., Hart, M. et al. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med 10, 638–642 (2004). https://doi.org/10.1038/nm1051

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