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

Cell Chem Biol .. 2022-02; 
Ee Von Moo , Kasper Harpsøe , Alexander S Hauser , Ikuo Masuho , Hans Bräuner-Osborne , David E Gloriam , Kirill A Martemyanov
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摘要

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 m... More

关键词

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