Preferential Coupling of Dopamine D(2S) and D(2L) Receptor Isoforms with G(i1) and G(i2) Proteins—In Silico Study

The dopamine D(2) 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 D(2) 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 D(2) 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.