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      Central Effects of 3-Iodothyronamine Reveal a Novel Role for Mitochondrial Monoamine Oxidases

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          Abstract

          3-Iodothyronamine (T1AM) is the last iodinated thyronamine generated from thyroid hormone alternative metabolism found circulating in rodents and in humans. So far, the physiopathological meaning of T1AM tissue levels is unknown. Much is instead known on T1AM pharmacological effects in rodents. Such evidence indicates that T1AM acutely modifies, with high potency and effectiveness, rodents’ metabolism and behavior, often showing inverted U-shaped dose–response curves. Although several possible targets for T1AM were identified, the mechanism underlying T1AM behavioral effects remains still elusive. T1AM pharmacokinetic features clearly indicate the central nervous system is not a preferential site for T1AM distribution but it is a site where T1AM levels are critically regulated, as it occurs for neuromodulators or neurotransmitters. We here summarize and discuss evidence supporting the hypothesis that central effects of T1AM derive from activation of intracellular and possibly extracellular pathways. In this respect, consisting evidence indicates the intracellular pathway is mediated by the product of T1AM phase-I non-microsomal oxidation, the 3-iodothryoacetic acid, while other data indicate a role for the trace amine-associated receptor, isoform 1, as membrane target of T1AM (extracellular pathway). Overall, these evidence might sustain the non-linear dose–effect curves typically observed when increasing T1AM doses are administered and reveal an interesting and yet unexplored link between thyroid, monoamine oxidases activity and histamine.

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

          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.
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            What are lipoproteins doing in the brain?

            Lipoproteins in plasma transport lipids between tissues, however, only high-density lipoproteins (HDL) appear to traverse the blood-brain barrier (BBB); thus, lipoproteins found in the brain must be produced within the central nervous system. Apolipoproteins E (ApoE) and ApoJ are the most abundant apolipoproteins in the brain, are mostly synthesized by astrocytes, and are found on HDL. In the hippocampus and other brain regions, lipoproteins help to regulate neurobehavioral functions by processes that are lipoprotein receptor-mediated. Moreover, lipoproteins and their receptors also have roles in the regulation of body weight and energy balance, acting through lipoprotein lipase (LPL) and the low-density lipoprotein (LDL) receptor-related protein (LRP). Thus, understanding lipoproteins and their metabolism in the brain provides a new opportunity with potential therapeutic relevance.
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              Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges.

              The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of interest in so-called trace amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs. Regulation of the dopaminergic system is particularly well understood and clinical testing of TAAR1 directed ligands for schizophrenia and psychiatric disorders have begun. In addition, pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function. This review critically discusses the current state of TAAR research, highlighting recent developments and focussing on human TAARs, their functions, and clinical implications. Current gaps in knowledge are identified, along with the research reagents and translational tools still required for continued advancement of the field. Through this, a picture emerges of an exciting field on the cusp of significant developments, with the potential to identify new therapeutic leads for some of the major unmet medical needs in the areas of neuropsychiatry and metabolic disorders.
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                Author and article information

                Contributors
                URI : https://frontiersin.org/people/u/462159
                URI : https://frontiersin.org/people/u/427530
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                06 June 2018
                2018
                : 9
                : 290
                Affiliations
                [1] 1Section of Pharmacology, Department of Neurology, Psychology, Drug Sciences and Child Health, University of Florence , Florence, Italy
                [2] 2Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence , Florence, Italy
                Author notes

                Edited by: Grazia Chiellini, Università degli Studi di Pisa, Italy

                Reviewed by: Maria Moreno, University of Sannio, Italy; Assunta Lombardi, Università degli Studi di Napoli Federico II, Italy

                *Correspondence: Laura Raimondi, laura.raimondi@ 123456unifi.it

                Specialty section: This article was submitted to Thyroid Endocrinology, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2018.00290
                5998184
                29928258
                2ba338de-52b9-46ef-82a0-34654fb93b61
                Copyright © 2018 Laurino, Landucci and Raimondi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 March 2018
                : 17 May 2018
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 43, Pages: 7, Words: 4810
                Categories
                Endocrinology
                Mini Review

                Endocrinology & Diabetes
                3-iodothyronamine,3-iodothyroacetic acid,histamine,trace amine-associated receptors,monoamine oxidases

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