DGPT news: Fritz Külz Award 2024

Le résumé fourni par la source

Keywords G protein-coupled receptors • Signaling regulation • Biased agonism G protein-coupled receptors (GPCRs) are prominent drug targets, due to their high accessibility at the plasma membrane and broad involvement in physiological processes (Hauser et al. 2017).As this family of receptors lack intrinsic enzymatic activity, GPCRs signal through interaction with downstream effectors, primarily heterotrimeric G proteins composed of a Gα subunit and a Gβγ dimer.The downstream signaling is regulated by a small family of kinases, namely GPCR kinases (GRKs), which phosphorylate intracellular receptor domains, facilitating β-arrestin recruitment.These scaffolding proteins mediate different functions, including receptor desensitization and internalization (Gurevich and Gurevich 2019).In previous years, G protein signaling and β-arrestinsupported functions have often been considered to be independent.The observation of reduced adverse opioid effects in β-arrestin2 knockout mice (Bohn et al. 1999) spurred research into biased agonism, aiming to selectively activate either G protein-or β-arrestin-mediated GPCR pathways to minimize off-target effects by developing biased agonists (Gesty-Palmer et al. 2006;DeWire and Violin 2011).β-arrestin-supported functions critically dependent on receptor phosphorylation, highlighting the importance of GRKs, which were previously understudied due to the limited availability of tools.Notably, however, in vitro studies revealed that GRK2/3 interact with the membrane-associated Gβγ subunits (Pitcher et al. 1995) to facilitate their translocation to the plasma membrane, where the activated receptors reside.More recently, we and others revealed differential GRK dependence among GPCRs for their regulation, utilizing advanced knockout systems to study individual GRK isoforms without endogenous background (Drube et al. 2022;

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