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J Mol Endocrinol. 2015 Jun;54(3):205-16. doi: 10.1530/JME-15-0003. Epub 2015 Apr 15.

3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling.

Author information

1
Institut für Experimentelle Pädiatrische EndokrinologieCharité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDepartment of Cell and Molecular BiologyKarolinska Institutet, Stockholm, SwedenInstitut für BiochemieMolekulare Biochemie, Medizinische Fakultät, University of Leipzig, Leipzig, GermanyInstitut für Experimentelle EndokrinologieCharité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
2
Institut für Experimentelle Pädiatrische EndokrinologieCharité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDepartment of Cell and Molecular BiologyKarolinska Institutet, Stockholm, SwedenInstitut für BiochemieMolekulare Biochemie, Medizinische Fakultät, University of Leipzig, Leipzig, GermanyInstitut für Experimentelle EndokrinologieCharité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany Institut für Experimentelle Pädiatrische EndokrinologieCharité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDepartment of Cell and Molecular BiologyKarolinska Institutet, Stockholm, SwedenInstitut für BiochemieMolekulare Biochemie, Medizinische Fakultät, University of Leipzig, Leipzig, GermanyInstitut für Experimentelle EndokrinologieCharité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
3
Institut für Experimentelle Pädiatrische EndokrinologieCharité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, GermanyDepartment of Cell and Molecular BiologyKarolinska Institutet, Stockholm, SwedenInstitut für BiochemieMolekulare Biochemie, Medizinische Fakultät, University of Leipzig, Leipzig, GermanyInstitut für Experimentelle EndokrinologieCharité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany heike.biebermann@charite.de.

Abstract

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.

KEYWORDS:

3-T1AM; G protein-coupled receptor; adrenergic receptor; thyronamine

PMID:
25878061
DOI:
10.1530/JME-15-0003
[Indexed for MEDLINE]

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