Ligand-directed bias of G protein signaling at the dopamine D2 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 Gi/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.

Automated summary

G-protein-coupled receptors (GPCRs) are the largest family of drug targets, but the understanding of how drugs act at GPCRs and contribute to the selectivity of G protein recognition is limited. In this study, the authors investigated the G protein selectivity profile of the dopamine D-2 receptor (D-2) and found that D-2 can discriminate between different members of the Gi/o family. The functional selectivity of D-2 varies across its ligands, which engage D-2 with distinct G protein coupling patterns. The study also identified residues in the D-2 binding pocket that shape these ligand-directed biases.