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

Abstract

Thyroxine (T(4)) 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, T(4) is enzymatically deiodinated to 3,5,3'-triiodothyronine (T(3)), a high-affinity ligand for the nuclear TH receptors TR alpha and TR beta, whose activation controls normal vertebrate development and physiology. T(3)-modulated transcription of target genes via activation of TR alpha and TR beta 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. Here we report the discovery of 3-iodothyronamine (T(1)AM), a naturally occurring derivative of TH that in vitro is a potent agonist of the G protein-coupled trace amine receptor TAR1. Administering T(1)AM in vivo induces profound hypothermia and bradycardia within minutes. T(1)AM 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.

The history of a developmental stage: Metamorphosis in chordates

“…Particularly, nongenomic TH effects were reported in mammals, involving TH receptors other than TR (Davis et al, 2007;Scanlan et al, 2004). However, the mode of action of those receptors is not well understood yet Scanlan et al, 2004).…”

The impact of scopolamine pretreatment on 3-iodothyronamine (T1AM) effects on memory and pain in mice

“…3-iodothyronamine (T1AM) is a trace amine circulating in mammals which is thought to be a by-product of T3 alternative metabolism (Scanlan et al, 2004). While the physiopathological meaning of T1AM tissue levels is largely unknown, pharmacological evidence suggests that T1AM induces effects similar but also opposite to those elicited by thyroid hormone without interacting at hormone receptors.…”

“…However, also T1AM has a complex pharmacodynamic profile, being considered a multi-target molecule since amine interaction at several Gprotein-coupled receptors including trace amine-associated receptors (TAAR1 and 8; Scanlan et al, 2004;Mühlhaus et al, 2014), α2 (Regard et al, 2007;Dinter et al 2015a), β2 adrenoreceptors (Dinter et al, 2015b) and ion channels (Lucius et al, 2015) have been reported. Until now, none of these targets has been recognized to be involved in the behavioral effects of low T1AM doses, including memory stimulation and hyperalgesia.…”

A Triple Play for Thyroid Hormone

“…The potential physiological roles for thyroid increased greatly with the discovery that thyronamines, decarboxylated and partially deiodinated metabolites of thyroid hormone, cause a 50% decrease in heart rate and an 8°C drop in body temperature in mice 30 min after dosing (1). Finding molecular mechanisms to explain these physiological effects is key to understanding and potentially exploiting this signaling pathway.…”

“…Although the concept of a thyroid metabolite as a neuromodulator has been mentioned previously (7), identifying the nature of the metabolite and its physiological relevance was not achieved. In previous work, a panel of thyronamines was synthesized with different degrees of iodination and screened against various biogenic amine receptors (1). A number of compounds were found to bind to an isoform of the trace amine-associated receptor (TAAR1), an orphan G-protein-coupled receptor that had not previously been linked with an endogenous ligand.…”