3-Iodothyronamine Induces Diverse Signaling Effects at Different Aminergic and Non-Aminergic G-Protein Coupled Receptors

Abstract

The thyroid hormone metabolite 3-iodothyronamine (3-T1AM) exerts diverse physiological reactions such as a decrease of body temperature, and negative inotropic and chronotropic effects. This observed pleomorphic effect in physiology can be barely explained by interaction with only one target protein such as the trace-amine receptor 1 (TAAR1), a class A G-protein coupled receptor (GPCR). Moreover, Taar1 knock-out mice still react to 3-T1AM through physiological responses with a rapid decrease in body temperature. These facts propelled our group and others to search for further targets for this molecule.The group of TAARs evolved early in evolution and, according to sequence similarities, they are closely related to adrenoceptors and other aminergic receptors. Therefore, several of these receptors were characterized by their potential to interplay with 3-T1AM. Indeed, 3-T1AM acts as a positive allosteric modulator on the beta2-adrenoceptor (ADRB2) and as a biased agonist on the serotonin receptor 1B (5HT1b) and the alpha2-adrenoceptor (ADRA2A). In addition, 3-T1AM was reported to be a weak antagonist at a non-aminergic muscarinic receptor (M3).These findings impressively reflect that such trace amines can unselectively and simultaneously function at different receptors expressed by one cell or at different tissues. In conclusion, the role of 3-T1AM is hypothesized to concert the fine-tuning of specific cell reactions by the accentuation of certain pathways dependent on distinct receptors. 3-T1AM acts as a regulator of signals by blocking, modulating, or inducing simultaneously distinct intracellular signaling cascades via different GPCRs.

3-Iodothyronamine Affects Thermogenic Substrates’ Mobilization in Brown Adipocytes

“…In this respect, no evidence is available yet. The affinity of T1AM for G protein-coupled receptors was reported in the µM range, while the concentration of T1AM here used was in the nM range [10].…”

“…T1AM systemically administered concentrates in several T3 target organs including the liver and the white adipose tissue, where it activates lipolysis with a concomitant inhibition of adipogenesis [9]. Among T1AM targets are membrane-bound [10], but also intracellular proteins, among which is mitochondrial F(0) F(1)-ATP synthase [11].…”

“…Adipocytes are the main cells of adipose tissues, currently considered as a novel immuno-endocrine organ [10], and represent the final differentiation state of pre-adipocytes. These cells are present in the stromal fraction of white and brown adipose tissue, and their differentiation is induced by stimuli present in the cell niche, including insulin and T3 [12].…”

Comparative Transcriptome Analysis Reveals the Potential Cardiovascular Protective Targets of the Thyroid Hormone Metabolite 3-Iodothyronamine (3-T1AM)

“…3-Iodothyronamine (3-T1AM) is a metabolite product of the thyroid hormones (TH) which exerts an opposite physiological function of classical TH such as a decrease of body temperature and metabolic rate in rodents [1]. Several studies have shown that 3-T1AM is presumed to act on various organs and different receptors rapidly [2]. Moreover, it has therapeutic potential for treatment of metabolic diseases [3], myocardial vascular diseases [4], and neurological diseases [5].…”

Thyroid Hormone Metabolite 3-Iodothyronamine (T1AM) Alleviates Hypoxia/Reoxygenation-Induced Cardiac Myocyte Apoptosis via Akt/FoxO1 Pathway

“…3-iodothyronamine (T1AM) is a metabolite product of the thyroid hormones (TH), which exert an opposite physiological function of classical TH such as a decrease of body temperature and metabolic rate in rodents [3]. Several studies have shown that T1AM is presumed to act on various organs and different receptors rapidly [4]. Moreover, it has therapeutic potential for treatment of metabolic diseases [5], myocardial vascular diseases [6], and neurological diseases [7].…”