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β-Arrestins bind to GPCRs in a conformationally sensitive manner and are known to regulate: 1) GPCR desensitization by inhibition of GPCR coupling to heterotrimeric G proteins, 2) GPCR endocytosis by promoting association of GPCR/β-arrestin complexes, and (3) arrestin-promoted signaling via the extensive adaptor functions of the β-arrestins. The β-arrestin-mediated signaling constitutes an important component of GPCR signaling in addition to the G protein-mediated signaling. Monitoring of β-arrestin recruitment to activated receptors has become a popular way to measure GPCR activity and is described as a ‘universal’ GPCR platform owing to the fact that it is G-protein independent, such that GPCRs will recruit β-arrestins regardless of the nature of the G protein to which they couple.

β-Arrestin recruitment is a ubiquitous mechanism of negative regulation of GPCR signaling, which has been demonstrated for almost all GPCRs. Recently, β-arrestins have been shown to act as signaling scaffolds for numerous pathways, such as Akt, c-Src, and ERK 1/2, in a G protein-independent manner. G protein and β-arrestin pathways were found to be distinct and could be pharmacologically modulated independently with “biased ligands”. Therefore, β-arrestin based assays are more interesting and it is possible to provide new insights into the functional selectivity of GPCR signaling. These insights may help eliminate undesirable side effects by activating certain pathways rather than others. Thus, β-arrestin recruitment assays provide novel, universal, and G-protein independent means for GPCR screening and drug discovery. Such assays are particularly useful for the screening of Gai-coupled GPCRs, which traditionally subjected to a small assay window in second messenger detection systems.

β-Arrestin Recruitment Assay Figure 1. Basic Schematic Diagram of β-arrestin recruitment and GPCR Endocytosis.

β-Arrestin Recruitment Assays at Creative Bioarray

Creative Bioarray offers four major in vitro assays to measure ligand-induced β-arrestin recruitment: PathHunter β-arrestin Assay, Tango GPCR Assay, LinkLight GPCR/β-arrestin Signaling Pathway Assay, and Transfluor Assay. The PathHunter β-arrestin Assay, Tango GPCR Assay System and LinkLight GPCR/β-arrestin Signaling Pathway Assays are homogenous, high throughput assays while the Transfluor Assay is a fluorescence image-based assay.

Highlights of Our β-Arrestin Recruitment Assays

  • G-protein independent β-arrestin signal readout
  • Assessing and identifying GPCR biased or functional-selective ligands
  • Assessing and identifying GPCR allosteric modulators
  • Screening old targets for new chemical matters
  • Validated with over 100 GPCRs to ensure all GPCR classes (Class I, II, III) are applicable
  • Single read-out is compatible with all GPCR subtypes, including Gi, Gs, Go, Gq, eliminating the need for multiple GPCR assays
  • Universal format requires no prior knowledge of G-protein, enabling orphan GPCR screening

References

  1. Van Koppen C. J. et al.; Arrestin-independent internalization of G protein-coupled receptors. Molecular Pharmacology, 2004, 66(3): 365-367.
  2. Wang T. et al.; Measurement of β-arrestin recruitment for GPCR targets. Assay Guidance Manual [Internet], 2017.
  3. Zhang R. et al.; Tools for GPCR drug discovery. Acta Pharmacologica Sinica, 2012, 33(3): 372-384.

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