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

Harmeier, A. and Obermueller, S. and Meyer, C. A. and Revel, F. G. and Buchy, D. and Chaboz, S. and Dernick, G. and Wettstein, J. G. and Iglesias, A. and Rolink, A. and Bettler, B. and Hoener, M. C.. (2015) Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers. European Neuropsychopharmacology, 25 (11). pp. 2049-2061.

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Official URL: https://edoc.unibas.ch/61398/

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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 beta-arrestin 2 (betaArr2) complementation assays we show that the interaction of TAAR1 with D2R reduced betaArr2 recruitment to D2R. In addition, we report that besides Galphas-protein signaling TAAR1 also signals via betaArr2. In the presence of D2R, cAMP signaling of TAAR1 was reduced while its betaArr2 signaling was enhanced, resulting in reduced GSK3beta activation. These results demonstrate that betaArr2 signaling may be an important pathway for TAAR1 function and that the activation of the TAAR1-D2R complex negatively modulates GSK3beta signaling. Given that patients with schizophrenia or bipolar disorder show increased GSK3beta signaling, such a reduction of GSK3beta signaling triggered by the interaction of D2R with activated TAAR1 further supports TAAR1 as a target for the treatment of psychiatric disorders.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Division of Physiology > Molecular Neurobiology Synaptic Plasticity (Bettler)
UniBasel Contributors:Bettler, Bernhard
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:19 Nov 2018 16:58
Deposited On:19 Nov 2018 16:58

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