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Dopamine D2 and 5-hydroxytryptamine 5-HT2A receptors assemble into functionally interacting heteromers Borroto-Escuela, Dasiel O. Romero-Fernandez, Wilber Tarakanov, Alexander O. Marcellino, Daniel Ciruela, Francisco Agnati, Luigi F. Fuxe, Kjell Dopamina - Receptores In view of the co-distribution of dopamine D2LR and 5-hydroxytryptamine 5-HT2A receptors (D2LR and 5-HT2AR, respectively) within inter alia regions of the dorsal and ventral striatum and their role as a target of antipsychotic drugs; in this study we assessed the potential existence of D2LR-5-HT2AR heteromers in living cells and the functional consequences of this interaction. Thus, by means of a proximity-based bioluminescence resonance energy transfer (BRET) approach we demonstrated that the D2LR and the 5-HT2AR form stable and specific heteromers when expressed in HEK293T mammalian cells. Furthermore, when the D2LR-5-HT2AR heteromeric signaling was analyzed we found that the 5-HT2AR-mediated phospholipase C (PLC) activation was synergistically enhanced by the concomitant activation of the D2LR as shown in a NFAT-luciferase reporter gene assay and a specific and significant rise of the intracellular calcium levels were observed when both receptors were simultaneously activated. Conversely, when the D2LR-mediated adenylyl cyclase (AC) inhibition was assayed we showed that costimulation of D2LR and 5-HT2AR within the heteromer led to inhibition of the D2LR functioning, thus suggesting the existence of a 5-HT2AR-mediated D2LR trans-inhibition phenomenon. Finally, a bioinformatics study reveals that the triplet amino acid homologies LLT (Leu-Leu-Thr) and AIS (Ala-Ile-Ser) in TM1 and TM3, respectively of the D2R-5-HT2AR may be involved in the receptor interface. Overall, the presence of the D2LR-5-HT2AR heteromer in discrete brain regions is postulated based on the existence of D2LR-5-HT2A receptor-receptor interactions in living cells and their codistribution inter alia in striatal regions. Possible novel therapeutic strategies for treatment of schizophrenia should be explored by targeting this heteromer. 2010-10-29 journal article Dasiel O. Borroto-Escuela, Wilber Romero-Fernandez, Alexander O. Tarakanov, Daniel Marcellino, Francisco Ciruela, Luigi F. Agnati, Kjell Fuxe, Dopamine D2 and 5-hydroxytryptamine 5-HT2A receptors assemble into functionally interacting heteromers, Biochemical and Biophysical Research Communications, Volume 401, Issue 4, 2010, Pages 605-610, ISSN 0006-291X, https://doi.org/10.1016/j.bbrc.2010.09.110. (https://www.sciencedirect.com/science/article/pii/S0006291X10018206) 10902104 https://doi.org/10.5281/zenodo.13859862 https://hdl.handle.net/10630/45002 10.1016/j.bbrc.2010.09.110 eng info:eu-repo/grantAgreement/Swedish_Research_Council//04X-715/SE/// info:eu-repo/grantAgreement/MICINN/SAF/SAF2008-01462/ES/// info:eu-repo/grantAgreement/MICINN/Consolider-Ingenio/CSD2008-00005/ES/// http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 International Elsevier