Inverse agonistic action of 3-iodothyronamine at the human trace amine-associated receptor 5

PLoS One. 2015 Feb 23;10(2):e0117774. doi: 10.1371/journal.pone.0117774. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • HEK293 Cells
  • Humans
  • Ligands
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / drug effects
  • Thyronines / pharmacology*

Substances

  • 3-iodothyronamine
  • Ligands
  • Receptors, G-Protein-Coupled
  • TAAR5 protein, human
  • Thyronines
  • trace amine-associated receptor 5, mouse

Grant support

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) project SPP1629 Thyroid Trans Act BI 893/5-1, KO 922/16-1, STA 1265/1-1, Graduate College 1208-2: Hormonal Regulation of Energy Metabolism, Body Weight and Growth, TP1 and TP3, and KL 2334/2-2. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.