Journal
JOURNAL OF MOLECULAR ENDOCRINOLOGY
Volume 54, Issue 3, Pages 205-216Publisher
BIOSCIENTIFICA LTD
DOI: 10.1530/JME-15-0003
Keywords
G protein-coupled receptor; adrenergic receptor; thyronamine; 3-T1AM
Categories
Funding
- priority program SPP1629 Thyroid Trans Act [BI 893/5-1, KO 922/16-1, STA 1265/1-1]
- Swedish Research Council
- Deutsche Forschungsgemeinschaft (DFG) Graduate College 1208/2 (Hormonal Regulation of Energy Metabolism, Body Weight and Growth) (TP1) [DFG HO5096/1-1]
- Deutsche Forschungsgemeinschaft (DFG) Graduate College 1208/2 (Hormonal Regulation of Energy Metabolism, Body Weight and Growth) (TP3) [DFG HO5096/1-1]
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Most in vivo effects of 3-iodothyronamine (3-T1AM) have been thus far thought to be mediated by binding at the trace amine-associated receptor 1 (TAAR1). Inconsistently, the 3-T1AM-induced hypothermic effect still persists in Taar1 knockout mice, which suggests additional receptor targets. In support of this general assumption, it has previously been reported that 3-T1AM also binds to the alpha-2A-adrenergic receptor (ADRA2A), which modulates insulin secretion. However, the mechanism of this effect remains unclear. We tested two different scenarios that may explain the effect: the sole action of 3-T1AM at ADRA2A and a combined action of 3-T1AM at ADRA2A and TAAR1, which is also expressed in pancreatic islets. We first investigated a potential general signaling modification using the label-free EPIC technology and then specified changes in signaling by cAMP inhibition and MAPKs (ERK1/2) determination. We found that 3-T1AM induced G(i/o) activation at ADRA2A and reduced the norepinephrine (NorEpi)-induced MAPK activation. Interestingly, in ADRA2A/TAAR1 hetero-oligomers, application of NorEpi resulted in uncoupling of the G(i/o) signaling pathway, but it did not affect MAPK activation. However, 3-T1AM application in mice over a period of 6 days at a daily dose of 5 mg/kg had no significant effects on glucose homeostasis. In summary, we report an agonistic effect of 3-T1AM on the ADRA2A-mediated G(i/o) pathway but an antagonistic effect on MAPK induced by NorEpi. Moreover, in ADRA2A/TAAR1 hetero-oligomers, the capacity of NorEpi to stimulate G(i/o) signaling is reduced by co-stimulation with 3-T1AM. The present study therefore points to a complex spectrum of signaling modification mediated by 3-T1AM at different G protein-coupled receptors.
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