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[Biased Signaling through G Protein-coupled Receptors].

Hitoshi Kurose1

  • 1Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University.

Yakugaku Zasshi : Journal of the Pharmaceutical Society of Japan
|October 2, 2022
PubMed
Summary

Biased agonists selectively activate G protein-coupled receptors (GPCRs) via G proteins or β-arrestins, offering potential for fewer side effects. Understanding these biased agonists is crucial for targeted drug development.

Keywords:
G proteinG protein-coupled receptorbiased activitypartial agonistβ-arrestin

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Area of Science:

  • Pharmacology
  • Cellular Biology
  • Molecular Signaling

Background:

  • G protein-coupled receptors (GPCRs) traditionally signal via G proteins.
  • β-arrestins, known regulators of GPCRs, can also mediate GPCR signaling.
  • Selective activation of these distinct signaling pathways is achievable with specific agonists.

Purpose of the Study:

  • To review the concept and implications of biased agonists in GPCR signaling.
  • To discuss the potential clinical benefits of biased agonists, such as reduced side effects.
  • To highlight the importance of assay systems in understanding biased agonism, particularly concerning partial agonists.

Main Methods:

  • Literature review of biased agonists and their mechanisms.
  • Discussion of agonist binding sites, including orthosteric and allosteric sites.
  • Analysis of how allosteric sites relate to biased agonist activity.

Main Results:

  • Biased agonists can selectively engage either G protein or β-arrestin pathways downstream of GPCRs.
  • Selective agonists offer a potential therapeutic advantage by minimizing off-target effects.
  • Allosteric binding sites play a significant role in the activity of biased agonists.

Conclusions:

  • Biased agonists represent a promising therapeutic strategy for GPCR-targeted drugs.
  • Further research and appropriate assay development are necessary to fully exploit biased agonism.
  • Understanding the nuances of biased agonism is key to advancing drug discovery for GPCRs.