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 obscure^2,3. 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.