Trace amine-associated receptor 1 activation silences GSK3β 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 beta-arrestin 2 ((beta Arr2) complementation assays we show that the interaction of TAAR1 with D2R reduced beta Arr2 recruitment to D2R. In addition, we report that besides Gas-protein signaling TAAR1 also signals via beta Arr2. In the presence of D2R, cAMP signaling of TAAR1 was reduced while its beta Arr2 signaling was enhanced, resulting in reduced GSK3 beta activation. These results demonstrate that beta Arr2 signaling may be an important pathway for TAAR1 function and that the activation of the TAAR1-D2R complex negatively modulates GSK3 beta signaling. Given that patients with schizophrenia or bipolar disorder show increased GSK3 beta signaling, such a reduction of GSK3 beta signaling triggered by the interaction of D2R with activated TAAR1 further supports TAAR1 as a target for the treatment of psychiatric disorders. (C) 2015 Elsevier B.V. and ECNP. All rights reserved.