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      Screening β-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors.

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          Abstract

          A variety of G-protein-coupled receptor (GPCR) screening technologies have successfully partnered a number of GPCRs with their cognate ligands. GPCR-mediated β-arrestin recruitment is now recognized as a distinct intracellular signaling pathway, and ligand-receptor interactions may show a bias toward β-arrestin over classical GPCR signaling pathways. We hypothesized that the failure to identify native ligands for the remaining orphan GPCRs may be a consequence of biased β-arrestin signaling. To investigate this, we assembled 10 500 candidate ligands and screened 82 GPCRs using PathHunter β-arrestin recruitment technology. High-quality screening assays were validated by the inclusion of liganded receptors and the detection and confirmation of these established ligand-receptor pairings. We describe a candidate endogenous orphan GPCR ligand and a number of novel surrogate ligands. However, for the majority of orphan receptors studied, measurement of β-arrestin recruitment did not lead to the identification of cognate ligands from our screening sets. β-Arrestin recruitment represents a robust GPCR screening technology, and ligand-biased signaling is emerging as a therapeutically exploitable feature of GPCR biology. The identification of cognate ligands for the orphan GPCRs and the extent to which receptors may exist to preferentially signal through β-arrestin in response to their native ligand remain to be determined.

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          Author and article information

          Journal
          J Biomol Screen
          Journal of biomolecular screening
          1552-454X
          1087-0571
          Jun 2013
          : 18
          : 5
          Affiliations
          [1 ] Medical Research Council Technology, Centre for Therapeutic Discovery, London, UK. craig.southern@tech.mrc.ac.uk
          Article
          1087057113475480
          10.1177/1087057113475480
          23396314

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