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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists / pharmacology*
  • Animals
  • Drug Evaluation, Preclinical
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Gene Expression
  • Glucose / metabolism
  • HEK293 Cells
  • Humans
  • Islets of Langerhans / metabolism
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Norepinephrine / antagonists & inhibitors
  • Norepinephrine / pharmacology
  • Receptors, Adrenergic, alpha-2 / genetics
  • Receptors, Adrenergic, alpha-2 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction
  • Thyronines / pharmacology*

Substances

  • 3-iodothyronamine
  • Adrenergic alpha-2 Receptor Agonists
  • Receptors, Adrenergic, alpha-2
  • Receptors, G-Protein-Coupled
  • Thyronines
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Glucose
  • Norepinephrine
  • Trace amine-associated receptor 1