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

Int J Mol Sci. 2020 Jan 9;21(2):436. doi: 10.3390/ijms21020436.

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 (D2S) and long (D2L) isoforms (differing with 29 amino acids insertion in the third intracellular loop, ICL3) and to study their coupling with Gi1 and Gi2 proteins. It was found that the D2L isoform preferentially couples with the Gi2 protein and D2S isoform with the Gi1 protein, which is in accordance with experimental data. Our findings give mechanistic insight into the interplay between isoforms of dopamine D2 receptors and Gi proteins subtypes, which is important to understand signaling by these receptors and their mediation by pharmaceuticals, in particular psychotic and antipsychotic agents.

Keywords: GPCRs; dopamine D2 receptor; molecular dynamics; molecular switches; principal component analysis.

MeSH terms

  • Computer Simulation*
  • Dopamine
  • GTP-Binding Protein alpha Subunits, Gi-Go / chemistry
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Principal Component Analysis
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Protein Structure, Secondary
  • Receptors, Dopamine D2 / chemistry
  • Receptors, Dopamine D2 / metabolism*
  • Water

Substances

  • Ligands
  • Protein Isoforms
  • Receptors, Dopamine D2
  • Water
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Dopamine