3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling.
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 α-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 Gi/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 Gi/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 Gi/o pathway but an antagonistic effect on MAPK induced by NorEpi. Moreover, in ADRA2A/TAAR1 hetero-oligomers, the capacity of NorEpi to stimulate Gi/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.
['Dinter|Juliane|J|', 'Mühlhaus|Jessica|J|', 'Jacobi|Simon Friedrich|SF|', 'Wienchol|Carolin Leonie|CL|', 'Cöster|Maxi|M|', 'Meister|Jaroslawna|J|', 'Hoefig|Carolin Stephanie|CS|', 'Müller|Anne|A|', 'Köhrle|Josef|J|', 'Grüters|Annette|A|', 'Krude|Heiko|H|', 'Mittag|Jens|J|', 'Schöneberg|Torsten|T|', 'Kleinau|Gunnar|G|', 'Biebermann|Heike|H|']
D058647:Adrenergic alpha-2 Receptor Agonists D000818:Animals D004353:Drug Evaluation, Preclinical D019206:GTP-Binding Protein alpha Subunits, Gi-Go D015870:Gene Expression D005947:Glucose D057809:HEK293 Cells D006801:Humans D007515:Islets of Langerhans D008297:Male D057507:Mice, 129 Strain D008810:Mice, Inbred C57BL D009638:Norepinephrine D018341:Receptors, Adrenergic, alpha-2 D043562:Receptors, G-Protein-Coupled D015398:Signal Transduction D013970:Thyronines
3-T1AM G protein-coupled receptor adrenergic receptor thyronamine