In view of the co-distribution of dopamine D(₂L)R and 5-hydroxytryptamine 5-HT(₂A) receptors (D(₂L)R and 5-HT(₂A)R, 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 D(₂L)R-5-HT(₂A)R 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 D(₂L)R and the 5-HT(₂A)R form stable and specific heteromers when expressed in HEK293T mammalian cells. Furthermore, when the D(₂L)R-5-HT(₂A)R heteromeric signaling was analyzed we found that the 5-HT(₂A)R-mediated phospholipase C (PLC) activation was synergistically enhanced by the concomitant activation of the D(₂L)R 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 D(2L)R-mediated adenylyl cyclase (AC) inhibition was assayed we showed that costimulation of D(₂L)R and 5-HT(₂A)R within the heteromer led to inhibition of the D(₂L)R functioning, thus suggesting the existence of a 5-HT(₂A)R-mediated D(₂L)R 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-HT(₂A)R may be involved in the receptor interface. Overall, the presence of the D(₂L)R-5-HT(₂A)R heteromer in discrete brain regions is postulated based on the existence of D(₂L)R-5-HT(₂A) 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.
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