Ligand-directed bias of G protein signaling at the dopamine D(2) receptor.

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 D(2) receptor (D(2)), a GPCR targeted by antipsychotic drugs. We show that D(2) 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 D(2) with a distinct G protein coupling pattern. Using structural modeling, receptor mutagenesis, and pharmacological evaluation, we identified residues in the D(2) binding pocket that shape these ligand-directed biases. We further provide pharmacogenomic evidence that natural variants in D(2) differentially affect its G protein biases in response to different ligands.