Ligand-directed bias of G protein signaling at the dopamine D2 receptor

Cell Chem Biol. 2022 Feb 17;29(2):226-238.e4. doi: 10.1016/j.chembiol.2021.07.004. Epub 2021 Jul 23.


G-protein-coupled receptors (GPCRs) represent the largest family of drug targets. Upon activation, GPCRs signal primarily via a diverse set of heterotrimeric G proteins. Most GPCRs can couple to several different G protein subtypes. However, how drugs act at GPCRs contributing to the selectivity of G protein recognition is poorly understood. Here, we examined the G protein selectivity profile of the dopamine D2 receptor (D2), a GPCR targeted by antipsychotic drugs. We show that D2 discriminates between six individual members of the Gi/o family, and its profile of functional selectivity is remarkably different across its ligands, which all engaged D2 with a distinct G protein coupling pattern. Using structural modeling, receptor mutagenesis, and pharmacological evaluation, we identified residues in the D2 binding pocket that shape these ligand-directed biases. We further provide pharmacogenomic evidence that natural variants in D2 differentially affect its G protein biases in response to different ligands.

Keywords: BRET; GPCR; biased signaling; cell signaling; dopamine; functional selectivity; heterotrimeric G protein.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology*
  • HEK293 Cells
  • Haloperidol / chemistry
  • Haloperidol / pharmacology*
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Receptors, Dopamine D2 / metabolism*
  • Signal Transduction / drug effects


  • Antipsychotic Agents
  • Ligands
  • Receptors, Dopamine D2
  • Haloperidol