Preferential Coupling of Dopamine D2S and D2L Receptor Isoforms with Gi1 and Gi2 Proteins—In Silico Study

Abstract

The dopamine D₂ receptor belongs to rhodopsin-like G protein-coupled receptors (GPCRs) and it is an important molecular target for the treatment of many disorders, including schizophrenia and Parkinson's disease. Here, computational methods were used to construct the full models of the dopamine D₂ receptor short (D_2S) and long (D_2L) isoforms (differing with 29 amino acids insertion in the third intracellular loop, ICL3) and to study their coupling with G_i1 and G_i2 proteins. It was found that the D_2L isoform preferentially couples with the G_i2 protein and D_2S isoform with the G_i1 protein, which is in accordance with experimental data. Our findings give mechanistic insight into the interplay between isoforms of dopamine D₂ receptors and G_i proteins subtypes, which is important to understand signaling by these receptors and their mediation by pharmaceuticals, in particular psychotic and antipsychotic agents.