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The Trace Amine-Associated Receptor 1 Agonist 3-Iodothyronamine Induces Biased Signaling at the Serotonin 1b Receptor.

ABSTRACT: Trace amine-associated receptors (TAARs) belong to the class A G-protein-coupled receptors (GPCR) and are evolutionary related to aminergic receptors. TAARs have been identified to mediate effects of trace amines. TAAR1 signaling is mainly mediated via activation of the Gs/adenylyl cyclase pathway. In addition to classical trace amines, TAAR1 can also be activated by the thyroid hormone derivative 3-iodothyronamine (3-T1AM). Pharmacological doses of 3-T1AM induced metabolic and anapyrexic effects, which might be centrally mediated in the hypothalamus in rodents. However, the observed anapyrexic effect of 3-T1AM persists in Taar1 knock-out mice which raises the question whether further GPCRs are potential targets for 3-T1AM and mediate the observed physiological effect. Anapyrexia has been observed to be related to action on aminergic receptors such as the serotonin receptor 1b (5-HT1b). This receptor primarily activates the Gi/o mediated pathway and PLC signaling through the G?? of Gi/o. Since the expression profiles of TAAR1 and 5-HT1b overlap, we questioned whether 3-T1AM may activate 5-HT1b. Finally, we also evaluated heteromerization between these two GPCRs and tested signaling under co-expressed conditions. In this study, we showed, that 3-T1AM can induce Gi/o signaling through 5-HT1b in a concentration of 10 ?M. Strikingly, at 5-HT1b the ligand 3-T1AM only activates the Gi/o mediated reduction of cAMP accumulation, but not PLC activation. Co-stimulation of 5-HT1b by both ligands did not lead to additive or synergistic signaling effects. In addition, we confirmed the capacity for heteromerization between TAAR1 and 5-HT1b. Under co-expression of TAAR1 and HTR1b, 3-T1AM action is only mediated via TAAR1 and activation of 5-HT1b is abrogated. In conclusion, we found evidence for 5-HT1b as a new receptor target for 3-T1AM, albeit with a different signaling effect than the endogenous ligand. Altogether, this indicates a complex interrelation of signaling effects between the investigated GPCRs and respective ligands.

SUBMITTER: Braunig J

PROVIDER: S-EPMC5857711 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Trace Amine-Associated Receptor 1 Agonist 3-Iodothyronamine Induces Biased Signaling at the Serotonin 1b Receptor.

Bräunig Julia J Dinter Juliane J Höfig Carolin S CS Paisdzior Sarah S Szczepek Michal M Scheerer Patrick P Rosowski Mark M Mittag Jens J Kleinau Gunnar G Biebermann Heike H

Frontiers in pharmacology 20180312

Trace amine-associated receptors (TAARs) belong to the class A G-protein-coupled receptors (GPCR) and are evolutionary related to aminergic receptors. TAARs have been identified to mediate effects of trace amines. TAAR1 signaling is mainly mediated via activation of the G<sub>s</sub>/adenylyl cyclase pathway. In addition to classical trace amines, TAAR1 can also be activated by the thyroid hormone derivative 3-iodothyronamine (3-T1AM). Pharmacological doses of 3-T1AM induced metabolic and anapyr ...[more]

PMID: 29593543

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Project description:Background and objectivesUlotaront (SEP-363856) is a trace amine-associated receptor 1 agonist with 5-HT1A receptor agonist activity currently in phase 3 clinical development for the treatment of schizophrenia. In this exploratory, flexibly dosed study, ulotaront was evaluated for the treatment of Parkinson disease psychosis (PDP).MethodsPatients with PDP requiring antipsychotic therapy were randomized, double-blind to ulotaront (25, 50, or 75 mg/d) or placebo. Mixed Model for Repeated Measures was used to assess change from baseline in the Scale for the Assessment of Positive Symptoms for Parkinson Disease (SAPS-PD) at 6 weeks (primary end point).ResultsThe efficacy analysis sample comprised 38 patients (ulotaront, n = 24; placebo, n = 14). SAPS-PD total scores were numerically reduced in ulotaront-treated vs placebo-treated patients from week 1 to week 6: Least squares mean (95% confidence interval) difference in change from baseline at week 6 was -1.1 (-6.5, 4.3, p = 0.681). PDP symptom complete remission (≥100% improvement [reduction] from baseline in SAPS-PD total score) was observed in 25% of ulotaront-treated vs 0% of placebo-treated patients. SAPS-PD and Neuropsychiatric Inventory hallucinations subscales were numerically reduced vs placebo, and SAPS-PD total scores were reduced in patients with greater cognitive impairment (baseline Mini-Mental State Examination [MMSE] scores ≤24). Ulotaront improved Scales for Outcomes in Parkinson Disease Sleep Scale - Daytime Sleepiness scores (p = 0.022). There was no worsening of Unified Parkinson Disease Rating Scale Part III motor score, MMSE, or vital signs. Adverse events (≥10%) with ulotaront vs placebo included hallucinations (24% vs 14%), confusional state (20% vs 14%), dizziness (16% vs 7%), nausea (12% vs 7%), and falls (12% vs 21%).DiscussionIn this exploratory pilot study, ulotaront may decrease PDP symptoms without worsening motor function, particularly in patients with cognitive impairment.Trial registration informationClinicalTrials.gov identifier: NCT02969369; submitted: November 17, 2016; study start date: December 31, 2016.Classification of evidenceThis Class II study was an exploratory pilot study that was underpowered to detect a statistically significant difference between ulotaront and placebo in the treatment of patients with Parkinson disease psychosis without worsening motor function.

Project description:Trace amine-associated receptors (TAARs) are a class of G-protein-coupled receptors found in mammals. While TAAR1 is expressed in several brain regions, all the other TAARs have been described mainly in the olfactory epithelium and the glomerular layer of the olfactory bulb and are believed to serve as a new class of olfactory receptors sensing innate odors. However, there is evidence that TAAR5 could play a role also in the central nervous system. In this study, we characterized a mouse line lacking TAAR5 (TAAR5 knockout, TAAR5-KO) expressing beta-galactosidase mapping TAAR5 expression. We found that TAAR5 is expressed not only in the glomerular layer in the olfactory bulb but also in deeper layers projecting to the limbic brain olfactory circuitry with prominent expression in numerous limbic brain regions, such as the anterior olfactory nucleus, the olfactory tubercle, the orbitofrontal cortex (OFC), the amygdala, the hippocampus, the piriform cortex, the entorhinal cortex, the nucleus accumbens, and the thalamic and hypothalamic nuclei. TAAR5-KO mice did not show gross developmental abnormalities but demonstrated less anxiety- and depressive-like behavior in several behavioral tests. TAAR5-KO mice also showed significant decreases in the tissue levels of serotonin and its metabolite in several brain areas and were more sensitive to the hypothermic action of serotonin 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propilamino)tetralin (8-OH-DPAT). These observations indicate that TAAR5 is not just innate odor-sensing olfactory receptor but also serves to provide olfactory input into limbic brain areas to regulate emotional behaviors likely via modulation of the serotonin system. Thus, anxiolytic and/or antidepressant action of future TAAR5 antagonists could be predicted. In general, "olfactory" TAAR-mediated brain circuitry may represent a previously unappreciated neurotransmitter system involved in the transmission of innate odors into emotional behavioral responses.

Dataset Information

The Trace Amine-Associated Receptor 1 Agonist 3-Iodothyronamine Induces Biased Signaling at the Serotonin 1b Receptor.

Publications

The Trace Amine-Associated Receptor 1 Agonist 3-Iodothyronamine Induces Biased Signaling at the Serotonin 1b Receptor.

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