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

Abstract

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 G_i/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.