Dopamine D2 and D4 receptor heteromerization and its allosteric receptor–receptor interactions

Dopamine D2 and D4 receptors partially codistribute in the dorsal striatum and appear to play a fundamental role in complex behaviors and motor function. The discovery of D2R–D4.xR (D4.2R, D4.4R or D4.7R) heteromers has been made in cellular models using co-immunoprecipitation, in situ Proximity Ligation Assays and BRET1 techniques with the D2R and D4.7R receptors being the least effective in forming heteromers. Allosteric receptor–receptor interactions in D2R–D4.2R and D2R–D4.4 R heteromers were observed using the MAPK assays indicating the existence of an enhancing allosteric receptor–receptor interaction in the corresponding heteromers between the two orthosteric binding sites. The bioinformatic predictions suggest the existence of a basic set of common triplets (ALQ and LRA) in the two participating receptors that may contribute to the receptor–receptor interaction interfaces.

Research highlights
► The discovery of D2R–D4.xR (D4.2R, D4.4R or D4.7R) heteromers has been made in cellular models.
► D2LR and D4.7R receptors being the least effective in forming heteromers.
► MAPK assays indicated the existence of an enhancing allosteric receptor–receptor interaction in the D2R–D4.2R and D2R–D4.4R heteromers.
► Bioinformatics analysis indicates the existence of a basic set of common triplets (ALQ and LRA) that may be involved in D2R–D4.xR heteromers.