lifesciences
Innopsys

Trace amine-associated receptor 1 activation silences GSK3B signaling of TAAR1 and D2R heteromers

Trace amine-associated receptor 1 (TAAR1) activation by selective endogenous agonists modulates dopaminergic neurotransmission. This results in antipsychotic-like behavior in vivo which might be initiated by an interaction of TAAR1 and dopamine D2L receptor (D2R). Here we analyzed the functional link between TAAR1 and D2R using highly potent and selective TAAR1 agonists, and newly generated tools such as TAAR1 knock-out and TAAR1 overexpressing rats as well as specific anti-rat TAAR1 antibodies. We provide data from co-immunoprecipitation experiments supporting a functional interaction of the two receptors in heterologous cells and in brain tissue. Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity. Using specific β-arrestin 2 (βArr2) complementation assays we show that the interaction of TAAR1 with D2R reduced βArr2 recruitment to D2R. In addition, we report that besides Gαs-protein signaling TAAR1 also signals via βArr2. In the presence of D2R, cAMP signaling of TAAR1 was reduced while its βArr2 signaling was enhanced, resulting in reduced GSK3β activation. These results demonstrate that βArr2 signaling may be an important pathway for TAAR1 function and that the activation of the TAAR1-D2R complex negatively modulates GSK3β signaling. Given that patients with schizophrenia or bipolar disorder show increased GSK3β signaling, such a reduction of GSK3β signaling triggered by the interaction of D2R with activated TAAR1 further supports TAAR1 as a target for the treatment of psychiatric disorders.

Credits:

Harmeier A1, Obermueller S2, Meyer CA2, Revel FG1, Buchi D1, Chaboz S1, Dernick G2, Wettstein JG1, Iglesias A3, Rolink A4, Bettler B5, Hoener MC6

  • 1. Neursciences, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. Grenzachestrasse 124, CH-4070 Basel, Switzerland
  • 2. Terapeutic Modalities, Discovery Technolgies, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. Grenzachestrasse 124, CH-4070 Basel, Switzerland
  • 3. Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. Grenzachestrasse 124, CH-4070 Basel, Switzerland
  • 4. Department of Biomedicine, Developmental and Molecula Immunology, Pharmazentrum, University of Basel, CH-4058 Basel, Switzerland
  • 5. Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Baser, CH-4056 Basel Switzerland
  • 6. Neurocience, Ophthalmology and Rare Diseases Discovery and Translational Areal, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. Grenzachestrasse 124, CH-4070 Basel, Switzerland

HEAD OFFICE

Parc d'activités Activestre
31390 Carbonne - FRANCE

CONTACT

Phone +33 561 971 974
Fax +33 561 971 975