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Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers.
Journal article

Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers.

  • Harmeier A Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
  • Obermueller S Therapeutic Modalities, Discovery Technologies, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
  • Meyer CA Therapeutic Modalities, Discovery Technologies, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
  • Revel FG Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
  • Buchy D Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
  • Chaboz S Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
  • Dernick G Therapeutic Modalities, Discovery Technologies, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
  • Wettstein JG Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
  • Iglesias A Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
  • Rolink A Department of Biomedicine, Developmental and Molecular Immunology, Pharmazentrum, University of Basel, CH-4058 Basel, Switzerland.
  • Bettler B Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland.
  • Hoener MC Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland. Electronic address: marius.hoener@roche.com.
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  • 2015-09-16
Published in:
  • European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. - 2015
Animals
Arrestins
Brain
CHO Cells
Cell Membrane
Cricetulus
Cyclic AMP
Gene Knockout Techniques
Glycogen Synthase Kinase 3
Glycogen Synthase Kinase 3 beta
HEK293 Cells
Humans
Rats, Transgenic
Rats, Wistar
Receptors, Dopamine D2
Receptors, G-Protein-Coupled
beta-Arrestin 2
beta-Arrestins
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.rero.ch/global/documents/53604
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