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.

Key words

3-T1AM - 3-iodothyronamine - G-protein coupled receptor - adrenoreceptors - aminergic receptors

Publication History

Article published online:
07 November 2019

• References

• 1 Scanlan TS, Suchland KL, Hart ME. et al. 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med 2004; 10: 638-642
• 2 Hoefig CS, Renko K, Piehl S. et al. Does the aromatic L-amino acid decarboxylase contribute to thyronamine biosynthesis?. Mol Cell Endocrinol 2012; 349: 195-201 DOI: 10.1016/j.mce.2011.10.024.
• 3 Hoefig CS, Wuensch T, Rijntjes E. et al. Biosynthesis of 3-iodothyronamine from T4 in murine intestinal tissue. Endocrinology 2015; 156: 4356-4364. DOI: 10.1210/en.2014-1499.
• 4 Zucchi R, Accorroni A, Chiellini G. Update on 3-iodothyronamine and its neurological and metabolic actions. Front Physiol 2014; 5: 402. DOI: 10.3389/fphys.2014.00402.
• 5 Zucchi R, Rutigliano G, Saponaro F. Novel thyroid hormones. Endocrine 2019; DOI: 10.1007/s12020-019-02018-4.
• 6 Chiellini G, Bellusci L, Sabatini M. et al. Thyronamines and analogues – The route from rediscovery to translational research on thyronergic amines. Mol Cell Endocrinol 2017; 458: 149-155. DOI: 10.1016/j.mce.2017.01.002.
• 7 Hoefig CS, Zucchi R, Kohrle J. Thyronamines and derivatives: Physiological relevance, pharmacological actions, and future research directions. Thyroid 2016; 26: 1656-1673. DOI: 10.1089/thy.2016.0178.
• 8 Accorroni A, Chiellini G, Origlia N. Effects of thyroid hormones and their metabolites on learning and memory in normal and pathological conditions. Curr Drug Metab 2017; 18: 225-236. DOI: 10.2174/1389200218666170116112407.
• 9 Kohrle J. Thyroid hormones and derivatives: Endogenous thyroid hormones and their targets. Methods Mol Biol 2018; 1801: 85-104. DOI: 10.1007/978-1-4939-7902-8_9.
• 10 Kohrle J. The colorful diversity of thyroid hormone metabolites. Eur. Thyroid J 2019; 8: 115-129. DOI: 10.1159/000497141.
• 11 Kohrle J, Biebermann H. 3-Iodothyronamine-A thyroid hormone metabolite with distinct target profiles and mode of action. Endocr Rev 2019; 40: 602-630. DOI: 10.1210/er.2018-00182.
• 12 Dhillo WS, Bewick GA, White NE. et al. The thyroid hormone derivative 3-iodothyronamine increases food intake in rodents. Diabetes, Obesity and Metabolism 2009; 11: 251-260. DOI: 10.1111/j.1463-1326.2008.00935.x.
• 13 Lindemann L, Ebeling M, Kratochwil NA. et al. Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics 2005; 85: 372-385 DOI: 10.1016/j.ygeno.2004.11.010.
• 14 Borowsky B, Adham N, Jones KA. et al. Trace amines: Identification of a family of mammalian G protein-coupled receptors. Proceedings of the National Academy of Sciences of the United States of America 2001; 98: 8966-8971. DOI: 10.1073/pnas.151105198.
• 15 John J, Kukshal P, Bhatia T. et al. Possible role of rare variants in trace amine associated receptor 1 in schizophrenia. Schizophr Res 2017; 189: 190-195. DOI: 10.1016/j.schres.2017.02.020.
• 16 Revel FG, Moreau JL, Gainetdinov RR. et al. TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci USA 2011; 108: 8485-8490. DOI: 10.1073/pnas.1103029108.
• 17 Wolinsky TD, Swanson CJ, Smith KE. et al. The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes, Brain and Behavior 2007; 6: 628-639 DOI: 10.1111/j.1601-183X.2006.00292.x.
• 18 Muhlhaus J, Dinter J, Jyrch S. et al. Investigation of naturally occurring single-nucleotide variants in human TAAR1. Front Pharmacol 2017; 8: 807 DOI: 10.3389/fphar.2017.00807.
• 19 Khajavi N, Mergler S, Biebermann H. 3-Iodothyronamine, a novel endogenous modulator of transient receptor potential melastatin 8?. Front Endocrinol (Lausanne) 2017; 8: 198. DOI: 10.3389/fendo.2017.00198.
• 20 Rutigliano G, Accorroni A, Zucchi R. The case for TAAR1 as a Modulator of central nervous system function. Front Pharmacol 2017; 8: 987. DOI: 10.3389/fphar.2017.00987.
• 21 Zucchi R, Ghelardoni S, Chiellini G. Cardiac effects of thyronamines. Heart Failure Reviews 2010; 15: 171-176 DOI: 10.1007/s10741-008-9120-z.
• 22 Liberles SD. Trace amine-associated receptors: ligands, neural circuits, and behaviors. Curr Opin Neurobiol 2015; 34: 1-7 DOI: 10.1016/j.conb.2015.01.001.
• 23 Gainetdinov RR, Hoener MC, Berry MD. Trace amines and their receptors. Pharmacol Rev 2018; 70: 549-620 DOI: 10.1124/pr.117.015305.
• 24 Bunzow JR, Sonders MS, Arttamangkul S. et al. Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Molecular Pharmacology 2001; 60: 1181-1188. DOI: 10.1124/mol.60.6.1181.
• 25 Babusyte A, Kotthoff M, Fiedler J. et al. Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2. J Leukoc Biol 2013; 93: 387-394. DOI: 10.1189/jlb.0912433.
• 26 Kovacevic M, McCoy J, Goren A. et al. Novel shampoo reduces hair shedding by contracting the arrector pili muscle via the trace amine-associated receptor. J Cosmet Dermatol 2019; DOI: 10.1111/jocd.13054.
• 27 Lindemann L, Meyer CA, Jeanneau K. et al. Trace amine-associated receptor 1 modulates dopaminergic activity. Journal of Pharmacology and Experimental Therapeutics 2008; 324: 948-956 DOI: 10.1124/jpet.107.132647.
• 28 Panas HN, Lynch LJ, Vallender EJ. et al. Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice. J Neurosci Res 2010; 88: 1962-1969. DOI: 10.1002/jnr.22367.
• 29 Dinter J, Muhlhaus J, Wienchol CL. et al. Inverse agonistic action of 3-iodothyronamine at the human trace amine-associated receptor 5. PLoS One 2015; 10: e0117774. DOI: 10.1371/journal.pone.0117774.
• 30 Morrison SF, Nakamura K. Central mechanisms for thermoregulation. Annu Rev Physiol 2019; 81: 285-308. DOI: 10.1146/annurev-physiol-020518-114546.
• 31 Braulke LJ, Klingenspor M, DeBarber A. et al. 3-Iodothyronamine: A novel hormone controlling the balance between glucose and lipid utilisation. J Comp Physiol B 2008; 178: 167-177. DOI: 10.1007/s00360-007-0208-x.
• 32 Chiellini G, Frascarelli S, Ghelardoni S. et al. Cardiac effects of 3-iodothyronamine: A new aminergic system modulating cardiac function. FASEB J 2007; 21: 1597-1608 DOI: 10.1096/fj.06-7474com.
• 33 Muhlhaus J, Dinter J, Nurnberg D. et al. Analysis of human TAAR8 and murine Taar8b mediated signaling pathways and expression profile. Int J Mol Sci 2014; 15: 20638-20655 DOI: 10.3390/ijms151120638.
• 34 Frascarelli S, Ghelardoni S, Chiellini G. et al. Cardioprotective effect of 3-iodothyronamine in perfused rat heart subjected to ischemia and reperfusion. Cardiovasc Drugs Ther 2011; 25: 307-313 DOI: 10.1007/s10557-011-6320-x.
• 35 Cody V, Meyer T, Dohler KD. et al. Molecular structure and biochemical activity of 3,5,3'-triiodothyronamine. Endocr Res 1984; 10: 91-99
• 36 Meyer T, Hesch RD. Triiodothyronamine - A beta-adrenergic metabolite of triiodothyronine?. Horm Metab Res 1983; 15: 602,606 DOI: 10.1055/s-2007-1018803.
• 37 Dinter J, Khajavi N, Muhlhaus J. et al. The multitarget ligand 3-iodothyronamine modulates beta-adrenergic receptor 2 signaling. Eur. Thyroid J 2015; 4: 21-29 DOI: 10.1159/000381801.
• 38 Dinter J, Muhlhaus J, Jacobi SF. et al. 3-iodothyronamine differentially modulates alpha-2A-adrenergic receptor-mediated signaling. J Mol Endocrinol 2015; 54: 205-216 DOI: 10.1530/JME-15-0003.
• 39 Kleinau G, Pratzka J, Nurnberg D. et al. Differential modulation of Beta-adrenergic receptor signaling by trace amine-associated receptor 1 agonists. PLoS One 2011; 6: e27073. DOI: 10.1371/journal.pone.0027073.
• 40 Khajavi N, Reinach PS, Slavi N. et al. Thyronamine induces TRPM8 channel activation in human conjunctival epithelial cells. Cell Signal 2015; 27: 315-325. DOI: 10.1016/j.cellsig.2014.11.015.
• 41 Roeder T. Tyramine and octopamine: Ruling behavior and metabolism. Annu Rev Entomol 2005; 50: 447-477 DOI: 10.1146/annurev.ento.50.071803.130404.
• 42 Burchett SA, Hicks TP. The mysterious trace amines: Protean neuromodulators of synaptic transmission in mammalian brain. Progress in Neurobiology 2006; 79: 223-246
• 43 Gompf HS, Greenberg JH, Aston-Jones G. et al. 3-Monoiodothyronamine: The rationale for its action as an endogenous adrenergic-blocking neuromodulator. Brain Res 2010; 1351: 130-140 DOI: 10.1016/j.brainres.2010.06.067.
• 44 Regard JB, Kataoka H, Cano DA. et al. Probing cell type-specific functions of Gi in vivo identifies GPCR regulators of insulin secretion. J Clin Invest 2007; 117: 4034-4043. DOI: 10.1172/JCI32994.
• 45 Lehmphul I, Hoefig CS, Kohrle J. 3-Iodothyronamine reduces insulin secretion in vitro via a mitochondrial mechanism. Mol Cell Endocrinol 2018; 460: 219-228. DOI: 10.1016/j.mce.2017.07.026.
• 46 Myers RD. Serotonin and thermoregulation: Old and new views. J Physiol (Paris) 1981; 77: 505-513
• 47 Hjorth S. Hypothermia in the rat induced by the potent serotoninergic agent 8-OH-DPAT. Journal of Neural Transmission 1985; 61: 131-135. DOI: 10.1007/bf01253058.
• 48 Gudelsky GA, Koenig JI, Meltzer HY. Thermoregulatory responses to serotonin (5-HT) receptor stimulation in the rat. Evidence for opposing roles of 5-HT2 and 5-HT1A receptors. Neuropharmacology 1986; 25: 1307-1313
• 49 Braunig J, Dinter J, Hofig CS. et al. The trace amine-associated receptor 1 agonist 3-iodothyronamine induces biased signaling at the serotonin 1b receptor. Front Pharmacol 2018; 9: 222. DOI: 10.3389/fphar.2018.00222.
• 50 Espinoza S, Ghisi V, Emanuele M. et al. Postsynaptic D2 dopamine receptor supersensitivity in the striatum of mice lacking TAAR1. Neuropharmacology 2015; 93: 308-313. DOI: 10.1016/j.neuropharm.2015.02.010.
• 51 Espinoza S, Salahpour A, Masri B. et al. Functional interaction between Trace Amine Associated Receptor 1 (TAAR1) and dopamine D2 receptor. Mol Pharmacol 2011; DOI: 10.1124/mol.111.073304.
• 52 Laurino A, Matucci R, Vistoli G. et al. 3-iodothyronamine (T1AM), a novel antagonist of muscarinic receptors. Eur J Pharmacol 2016; 793: 35-42. DOI: 10.1016/j.ejphar.2016.10.027.