PT  - JOURNAL ARTICLE
AU  - Stefano Espinoza
AU  - Ali Salahpour
AU  - Bernard Masri
AU  - Tatyana D. Sotnikova
AU  - Mirko Messa
AU  - Larry S. Barak
AU  - Marc G. Caron
AU  - Raul R. Gainetdinov
TI  - Functional Interaction between Trace Amine-Associated Receptor 1 and Dopamine D2 Receptor
AID  - 10.1124/mol.111.073304
DP  - 2011 Sep 01
TA  - Molecular Pharmacology
PG  - 416--425
VI  - 80
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/80/3/416.short
4100  - http://molpharm.aspetjournals.org/content/80/3/416.full
SO  - Mol Pharmacol2011 Sep 01; 80
AB  - The ability of dopamine receptors to interact with other receptor subtypes may provide mechanisms for modulating dopamine-related functions and behaviors. In particular, there is evidence suggesting that the trace amine-associated receptor 1 (TAAR1) affects the dopaminergic system by regulating the firing rate of dopaminergic neurons or by altering dopamine D2 receptor (D2R) responsiveness to ligands. TAAR1 is a Gαs protein-coupled receptor that is activated by biogenic amines, “trace amines,” such as β-phenylethylamine (β-PEA) and tyramine that are normally found at low concentrations in the mammalian brain. In the present study, we investigated the biochemical mechanism of interaction between TAAR1 and D2R and the role this interaction plays in D2R-related signaling and behaviors. Using a bioluminescence resonance energy transfer biosensor for cAMP, we demonstrated that the D2R antagonists haloperidol, raclopride, and amisulpride were able to enhance selectively a TAAR1-mediated β-PEA increase of cAMP. Moreover, TAAR1 and D2R were able to form heterodimers when coexpressed in human embryonic kidney 293 cells, and this direct interaction was disrupted in the presence of haloperidol. In addition, in mice lacking TAAR1, haloperidol-induced striatal c-Fos expression and catalepsy were significantly reduced. Taken together, these data suggest that TAAR1 and D2R have functional and physical interactions that could be critical for the modulation of the dopaminergic system by TAAR1 in vivo.