title: Trace amine-associated receptor 1 activation silences GSK3β signaling of TAAR1 and D2R heteromers.
abstract: 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.
authors.affiliation: Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Anja
authors.initials: A
authors.lastname: Harmeier
authors.affiliation: Therapeutic Modalities, Discovery Technologies, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Obermueller
authors.affiliation: Therapeutic Modalities, Discovery Technologies, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Claas A
authors.initials: CA
authors.lastname: Meyer
authors.affiliation: Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Florent G
authors.initials: FG
authors.lastname: Revel
authors.affiliation: Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Daniele
authors.initials: D
authors.lastname: Buchy
authors.affiliation: Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Chaboz
authors.affiliation: Therapeutic Modalities, Discovery Technologies, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Gregor
authors.initials: G
authors.lastname: Dernick
authors.affiliation: Neuroscience, Ophthalmology and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
authors.affiliation: Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Antonio
authors.initials: A
authors.lastname: Iglesias
authors.affiliation: Department of Biomedicine, Developmental and Molecular Immunology, Pharmazentrum, University of Basel, CH-4058 Basel, Switzerland.
authors.forename: Antonius
authors.initials: A
authors.lastname: Rolink
authors.affiliation: Department of Biomedicine, Institute of Physiology, Pharmazentrum, University of Basel, CH-4056 Basel, Switzerland.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Bettler
authors.affiliation: 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.
authors.forename: Marius C
authors.initials: MC
authors.lastname: Hoener
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D055786:Gene Knockout Techniques; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D055647:Rats, Transgenic; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000095383:Trace Amine-Associated Receptors
chemical_list: D019390:Arrestins; D000242:Cyclic AMP; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000095383:Trace Amine-Associated Receptors; C000605254:ARRB2 protein, human; C000605257:Arrb2 protein, rat; C581293:DRD2 protein, human; C000605506:GSK3B protein, human; C000605508:Gsk3b protein, rat