P2.09. ACTIVATION OF TARCE-AMINE ASSOCIATED RECEPTOR (TAAR1): MOLECULAR CHANGES INDUCED BY TAAR1 AGONISTS
Sofiya Kokhanovska1,2,3, Kamila Skieterska1, Katarzyna Skowrońska1, Aleksandra Moroz1, Michał Mroczkiewicz1, Mateusz Mach1, Damian Tuz1, Damian Smuga1, Wojciech Pietruś1, Krzysztof Dubiel1, Mikołaj Matłoka1, Leonora Bużańska2
1 Celon Pharma S.A., R&D Centre, 15 Marymoncka St., Kazun Nowy, Poland
2 Mossakowski Medical Research Institute, Polish Academy of Sciences, Department of Stem Cell Bioengineering, 5 Pawińskiego St., Warsaw, Poland
3 Doctoral School of Translational Medicine, Centre of Postgraduate Medical Education, 99/103 Marymoncka St., Warsaw, Poland
INTRODUCTION: TAAR1 is a receptor for trace amines modulating dopaminergic, glutamatergic and serotoninergic neural transmission. In phase II clinical trials dual TAAR1 and 5HT1A receptor agonist, ulotaront, ameliorated both positive and negative symptoms of schizophrenia and did not cause extrapyramidal and metabolic side effects. Thus TAAR1 is an attractive therapeutic target for neuropsychiatric disorders. Molecular events induced by TAAR1 agonists are not fully elucidated. Recent studies suggest that activation of TAAR1 could induce Gαs, Gαq, Gαi and Gα12 or β-arrestin recruitment. Moreover, TAAR1 agonists could elevate ERK1/2 and CREB phosphorylation in PKA dependent manner. They could also activate Akt-GSK-3β pathway which may be involved in antipsychotic effect of current medicines.
AIM(S): Aim of this study is to reveal a signaling pathways induced upon TAAR1 activation by reference and novel compounds.
METHOD(S): We use Hit Hunter assay for studying cAMP signaling in cell line with overexpression of human TAAR1. Phosphorylation levels of ERK1/2, CREB, Akt and GSK-3β were measured using western blot analysis. β-PEA, ulotaront and novel TAAR1 agonist were selected for molecular studies. Cells were additionally treated with various inhibitors to determine cell signaling pathways involved in receptor activation.
RESULTS: Activation of TAAR1 by selected agonists results in increased intracellular cAMP and phosphorylation of ERK1/2 and CREB proteins which is blocked by PKA inhibitor. Additionally, elevation of Akt and GSK-3β proteins phosphorylation was observed.
CONCLUSIONS: Here we revealed that PKA regulates TAAR1 signaling induced by β-PEA, ulotaront and novel TAAR1 agonist. Moreover, we confirmed that TAAR1 agonists modulate activity of Akt and GSK-3β. Further studies are needed to elucidate the link between activation of these signaling events and antipsychotic effects of TAAR1 agonists.
FINANCIAL SUPPORT: Implementation doctorate program DWD/6/0431/2022; Celon Pharma S.A.