Details

Autor(en) / Beteiligte

• Von Moo, Ee
• Harpsøe, Kasper
• Hauser, Alexander S.
• Masuho, Ikuo
• Bräuner-Osborne, Hans
• Gloriam, David E.
• Martemyanov, Kirill A.

Titel

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

Ist Teil von

• Cell chemical biology, 2022-02, Vol.29 (2), p.226-238.e4

Ort / Verlag

Elsevier Ltd

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. [Display omitted] •The D2 dopamine receptor differentially activates various Gαi/o proteins•Dopamine and antipsychotic drugs produce distinct Gα activation profiles•Rationally designed mutations in D2 can override G protein biases•Genetic variants in D2 alter its G protein preferences Von Moo et al. report that the dopamine D2 receptor engages different G proteins when activated by dopamine and antipsychotics. They elucidate the structural mechanism underlying G protein bias and show how it can be altered by natural variants and rationally designed mutations.