title: Inverse agonistic action of 3-iodothyronamine at the human trace amine-associated receptor 5.
abstract: Application of 3-iodothyronamine (3-T1AM) results in decreased body temperature and body weight in rodents. The trace amine-associated receptor (TAAR) 1, a family A G protein-coupled receptor, is a target of 3-T1AM. However, 3-T1AM effects still persist in mTaar1 knockout mice, which suggest so far unknown further receptor targets that are of physiological relevance. TAAR5 is a highly conserved TAAR subtype among mammals and we here tested TAAR5 as a potential 3-T1AM target. First, we investigated mouse Taar5 (mTaar5) expression in several brain regions of the mouse in comparison to mTaar1. Secondly, to unravel the full spectrum of signaling capacities, we examined the distinct Gs-, Gi/o-, G12/13-, Gq/11- and MAP kinase-mediated signaling pathways of mouse and human TAAR5 under ligand-independent conditions and after application of 3-T1AM. We found overlapping localization of mTaar1 and mTaar5 in the amygdala and ventromedial hypothalamus of the mouse brain. Second, the murine and human TAAR5 (hTAAR5) display significant basal activity in the Gq/11 pathway but show differences in the basal activity in Gs and MAP kinase signaling. In contrast to mTaar5, 3-T1AM application at hTAAR5 resulted in significant reduction in basal IP3 formation and MAP kinase signaling. In conclusion, our data suggest that the human TAAR5 is a target for 3-T1AM, exhibiting inhibitory effects on IP3 formation and MAP kinase signaling pathways, but does not mediate Gs signaling effects as observed for TAAR1. This study also indicates differences between TAAR5 orthologs with respect to their signaling profile. In consequence, 3-T1AM-mediated effects may differ between rodents and humans.
authors.affiliation: Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Dinter
authors.affiliation: Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mühlhaus
authors.affiliation: Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Carolin Leonie
authors.initials: CL
authors.lastname: Wienchol
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz-Zentrum München, German Research Center for Environmental Health, München, Germany.
authors.forename: Chun-Xia
authors.initials: CX
authors.lastname: Yi
authors.affiliation: Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Nürnberg
authors.affiliation: Institute for Diabetes and Obesity, Helmholtz-Zentrum München, German Research Center for Environmental Health, München, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Morin
authors.affiliation: Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
authors.affiliation: Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Köhrle
authors.affiliation: Institut für Biochemie, Molekulare Biochemie, Medizinische Fakultät, University of Leipzig, Leipzig, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
authors.affiliation: Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Tschöp
authors.affiliation: Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Krude
authors.affiliation: Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
authors.affiliation: Institut für Experimentelle Pädiatrische Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
mesh_terms: D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013970:Thyronines / Q000494:pharmacology*; D000095383:Trace Amine-Associated Receptors
chemical_list: D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D013970:Thyronines; C487948:3-iodothyronamine; C583307:TAAR5 protein, human; D000095383:Trace Amine-Associated Receptors; C582062:TAAR5 protein, mouse