Genetic variants in dopamine receptors influence on heterodimerization in the context of antipsychotic drug action.

Human dopamine D2 receptor (D2R) gene has polymorphic variants, three of them alter its amino acid sequence: Val96Ala, Pro310Ser and Ser311Cys. Their functional role never became the object of extensive studies, even though there are some evidence that they correlate with schizophrenia. The present work reviews data indicating that these mutations play a role in dimer formation with dopamine D1 receptor (D1R), with the strongest effect observed for Ser311Cys variant. Similarly, the affinity for antipsychotic drugs of this genetic variant depends on whether it is expressed together with D1R or not. Better understanding of altered ability of genetic variants of D2R to form dimers with D1R, as well as of altered affinity for antipsychotic drugs, depending on the absence or presence of the second dopamine receptor is of great importance-since these two receptors are not always co-expressed in the same cell. It may well be that targeting new compounds toward the D1R-D2R dimers, which the most probably form under conditions of excessive dopamine release, will result in antipsychotic drugs devoid of serious side effects.