Use of the BRET 7TM receptor/beta-arrestin assay in drug discovery and screening.

To perform functional cell-based screening assays on seven-transmembrane (7TM) receptors, also known as G-protein coupled receptors, at least three distinct assays are currently needed to screen for G(alphas), G(alphai/0) or G(alphaq/11) signaling receptors. Therefore, there has long been a desire for a universal screening assay that could be used to screen all 7TM receptors independent of their signaling pathway. The receptor/beta-arrestin interaction is common to virtually all 7TM receptors. Therefore, an assay based on this interaction should achieve just that. Bioluminescence resonance energy transfer technology can be used to measure the receptor/beta-arrestin interaction in living cells but due to various technical and biological reasons, the use of the technology for compound screening has been limited. The recent development of beta-arrestin mutants that significantly improve the assay signal, in combination with new improved instrumentation, has transformed bioluminescence resonance energy transfer technology from being a highly specialized research tool in molecular pharmacology to a more drug screening-friendly technique that is useful in an industrial setting.