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.
Explore Eurofins DiscoverX β-Arrestin Products and Services
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.
- Read application notes:
- Uncover Novel G-Protein or Arrestin-Biased Ligands Using a Suite of GPCR Signaling Cell-Based Assays: A Study of Biased Agonism on Opioid Receptors
- Quantify GPCR Endocytosis and Recycling with PathHunter GPCR Internalization Assays – Analyzing Therapeutics for Opioid and Cholecystokinin Receptors
- Automating Cell-Based Bioassays on Tecan®’s Fluent Automation Workstation: Measuring β-Arrestin Recruitment of Cannabinoid Receptor 1 and related blog Use of Automated Functional, Cell-Based Bioassays (a PathHunter® CNR1 Bioassay study)
- 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.
