title: 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.
authors.affiliation: Department of Pharmaceutical Chemistry and Cellular & Molecular Pharmacology, University of California-San Francisco, San Francisco, California 94143-2280, USA. scanlan@cgl.ucsf.edu
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Scanlan
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Suchland
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hart
authors.forename: Grazia
authors.initials: G
authors.lastname: Chiellini
authors.forename: Yong
authors.initials: Y
authors.lastname: Huang
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Kruzich
authors.forename: Sabina
authors.initials: S
authors.lastname: Frascarelli
authors.forename: Dane A
authors.initials: DA
authors.lastname: Crossley
authors.forename: James R
authors.initials: JR
authors.lastname: Bunzow
authors.forename: Simonetta
authors.initials: S
authors.lastname: Ronca-Testoni
authors.forename: Emil T
authors.initials: ET
authors.lastname: Lin
authors.forename: Daniel
authors.initials: D
authors.lastname: Hatton
authors.forename: Riccardo
authors.initials: R
authors.lastname: Zucchi
authors.forename: David K
authors.initials: DK
authors.lastname: Grandy
mesh_terms: D000818:Animals; D001831:Body Temperature; D001923:Brain Chemistry; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007035:Hypothermia; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D051381:Rats; D017208:Rats, Wistar; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013970:Thyronines / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism*; D013974:Thyroxine / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D000095383:Trace Amine-Associated Receptors
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D011988:Receptors, Thyroid Hormone; D013970:Thyronines; D013974:Thyroxine; D000095383:Trace Amine-Associated Receptors; C487948:3-iodothyronamine; C004547:thyronamine