Abstract
Trace amine-associated receptors (TAARs) belong to the class A G-protein-coupled receptors (GPCR) and are evolutionary related to aminergic receptors. TAARs have been identified to mediate effects of trace amines. TAAR1 signaling is mainly mediated via activation of the Gs/adenylyl cyclase pathway. In addition to classical trace amines, TAAR1 can also be activated by the thyroid hormone derivative 3-iodothyronamine (3-T1AM). Pharmacological doses of 3-T1AM induced metabolic and anapyrexic effects, which might be centrally mediated in the hypothalamus in rodents. However, the observed anapyrexic effect of 3-T1AM persists in Taar1 knock-out mice which raises the question whether further GPCRs are potential targets for 3-T1AM and mediate the observed physiological effect. Anapyrexia has been observed to be related to action on aminergic receptors such as the serotonin receptor 1b (5-HT1b). This receptor primarily activates the Gi/o mediated pathway and PLC signaling through the Gβγ of Gi/o. Since the expression profiles of TAAR1 and 5-HT1b overlap, we questioned whether 3-T1AM may activate 5-HT1b. Finally, we also evaluated heteromerization between these two GPCRs and tested signaling under co-expressed conditions. In this study, we showed, that 3-T1AM can induce Gi/o signaling through 5-HT1b in a concentration of 10 μM. Strikingly, at 5-HT1b the ligand 3-T1AM only activates the Gi/o mediated reduction of cAMP accumulation, but not PLC activation. Co-stimulation of 5-HT1b by both ligands did not lead to additive or synergistic signaling effects. In addition, we confirmed the capacity for heteromerization between TAAR1 and 5-HT1b. Under co-expression of TAAR1 and HTR1b, 3-T1AM action is only mediated via TAAR1 and activation of 5-HT1b is abrogated. In conclusion, we found evidence for 5-HT1b as a new receptor target for 3-T1AM, albeit with a different signaling effect than the endogenous ligand. Altogether, this indicates a complex interrelation of signaling effects between the investigated GPCRs and respective ligands.
| Original language | English |
|---|---|
| Article number | 222 |
| Journal | Frontiers in Pharmacology |
| Volume | 9 |
| Issue number | MAR |
| DOIs | |
| Publication status | Published - 12.03.2018 |
Funding
This work was supported by the Deutsche Forschungsgemeinschaft priority program Thyroid Trans Act SPP1629 BI893/5-2 to HB and Mi1242/4-1 to JM, SFB740-B6 to PS, SFB1078-B6 to PS, and DFG Cluster of Excellence 'Unifying Concepts in Catalysis' (Research Field D/E to GK and PS).The authors thank Sabine Jyrch and Cigdem Cetindag (Charit?, Institute of Pediatric Experimental Endocrinology) for technical assistance. We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charit?-Universit?tsmedizin Berlin.
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
