Innovating Your Drug Discovery

Why Study GPCR Arrestin Recruitment?

GPCR β-Arrestin Signaling

Arrestins are ubiquitously expressed and function in the activation of GPCRs, desensitization of most 7-transmembrane receptors (7-TMs), and regulation of other signaling molecules such as protein kinases.

There are currently four known arrestins:

  • Visual and cone arrestins play a major role in photoreceptor cell regulation
  • β-arrestin1 and 2 interact with the majority of commonly targeted 7-TMs

For GPCRs, ligand-induced β-arrestin (1 or 2) recruitment activates signaling cascades independently of G-protein signaling to provide a stoichiometric, non-amplified signal.  β-arrestin recruitment assays offer an easy to use alternative to second messenger cAMP and calcium G-protein dependent pathways to enable enhanced profiles of compound pharmacology –  a universal assay that expands opportunities for development of novel drugs.

Benefits of a Non-amplified System

The β-arrestin signaling pathway is an ideal system for discovering antagonists, studying GPCR deorphanization, and dissecting ligand pharmacology differences.

cAMP Second Messenger G-protein Dependent Signaling Pathway

An amplified system that can lead to rapid saturation using low levels of GPCR activating ligands.  This is a more sensitive system based on partial receptor occupancy giving a full signal due to the amplified signaling event (receptor reserve phenomena) after ligand activation.  Agonist can easily be detected since it does not take much agonist to obtain a full signal, but differentiating partial from full agonists can be difficult, and cAMP assays tend to have lower sensitivities to antagonists than do arrestin assays.

β-arrestin Signaling Pathway

A stoichiometric (1 receptor: 1 ligand), non-amplified system that requires full ligand occupancy of the ligand bound to the receptor to give a full signal. This leads to a lower sensitivity to agonists, but improved ability to detect differences of efficacy between agonists, and superior sensitivity for antagonists (compared to second messenger systems). This makes β-arrestin an ideal system for fine tuning GPCR biology when screening antagonists as well as for deorphanizing GPCRs and distinguishing between full, super, and partial agonists.

 Multiple Applications of β-Arrestin Assays

  • Perform multiple pathway analysis in the same cell line
  • Uncover unique pharmacology
  • Correctly rank order ligands
  • Deorphanize GPCRs
  • Evaluate difficult GPCRs
  • Compare ligand responses in different species receptors (orthologs)
  • Study mutant or isoform differences
  • Investigate tissue specific variations using different cell types
  • Enable ligand bias studies

  β-Arrestin Resources

  • Learn how DiscoverX can help you research β-arrestin applications and more through the use of cell-based assays. DiscoverX provides a complete set of tools to analyze β-arrestin biology. The PathHunter® β-arrestin assays and reagents offer a powerful and universal screening and profiling platform that can be used for virtually any Gi-, Gs, or Gq-coupled receptor.
  • Discover other β-arrestin applications through customer publications. These publications cover many class A and B GPCRs where researchers used small molecule and/or biologic ligands. The publications include basic research experiments and drug discovery studies from assay development through screening and preclinical programs.
  • Publications used in this article:
    • Lundstrom, K., “New winds in GPCR-based drug discovery.” Future Medicinal Chemistry, 2016; 8(6): 605-608.
    • Bassoni, D., et. al., “Measurements of β-arrestin recruitment to activated seven transmembrane receptors using enzyme complementation.” Methods Mol. Biol. 2012; 897: 181-203.