title: 3-iodothyronamine differentially modulates α-2A-adrenergic receptor-mediated signaling.
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.
authors: 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.
authors: Juliane
authors: J
authors: Dinter
authors: 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.
authors: Jessica
authors: J
authors: Mühlhaus
authors: 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.
authors: Simon Friedrich
authors: SF
authors: Jacobi
authors: 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.
authors: Carolin Leonie
authors: CL
authors: Wienchol
authors: 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.
authors: Maxi
authors: M
authors: Cöster
authors: 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.
authors: Jaroslawna
authors: J
authors: Meister
authors: 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.
authors: Carolin Stephanie
authors: CS
authors: Hoefig
authors: 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.
authors: Anne
authors: A
authors: Müller
authors: 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.
authors: Josef
authors: J
authors: Köhrle
authors: 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.
authors: Annette
authors: A
authors: Grüters
authors: 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.
authors: Heiko
authors: H
authors: Krude
authors: 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.
authors: Jens
authors: J
authors: Mittag
authors: 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.
authors: Torsten
authors: T
authors: Schöneberg
authors: 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.
authors: Gunnar
authors: G
authors: Kleinau
authors: 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.
authors: Heike
authors: H
authors: Biebermann
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D004353:Drug Evaluation, Preclinical; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D013970:Thyronines / Q000494:pharmacology*; D000095383:Trace Amine-Associated Receptors
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D005947:Glucose; D009638:Norepinephrine; D018341:Receptors, Adrenergic, alpha-2; D043562:Receptors, G-Protein-Coupled; D013970:Thyronines; D000095383:Trace Amine-Associated Receptors; C487948:3-iodothyronamine
keywords: 3-T1AM; G protein-coupled receptor; adrenergic receptor; thyronamine