Probing the Functional Selectivity of β-adrenergic Receptors Reveals New Signaling Modes and Potential Therapeutic Applications

Emma van der Westhuizen, Wayne Stallaert, Brigitte Murat, Martin Audet, Segolène Galandrin, Monique Lagacé, Michel Bouvier

Research output: Chapter in Book/Report/Conference proceedingConference PaperOtherpeer-review


BACKGROUND: In recent years, it has become clear that GPCRs are not uni-dimensional switches that turn ‘on’ or‘off’ single signaling pathways. Instead, each receptor can engage multiple signaling cascades that may or may not involve G protein activation. Individual ligands can have differential efficacies toward specific subsets of these signaling effectors. This phenomenon known as ligand-biased signaling or functional selectivity offers interesting opportunities to develop compound with increased selectivity profiles but present important challenges for the drug discovery process.
OBJECTIVES: Using fluorescence and bioluminescence resonance energy transfer (FRET-BRET)-based biosensors that we recently developed as well as label-free impedance measurements, the present study was aimed at monitoring multiple signaling pathways triggered by the β-adrenergic receptors in living cells and to assess the molecular determinants of ligand-biased signaling.
METHODS AND RESULTS: Using BRET- and FRET-based assays that monitor multiple signaling pathways we unraveled new signaling modes for β-adrenergic receptors (βAR) ligands and classified them into distinct subclasses that display unique signaling efficacy profiles toward different proximal effectors (Gi, Gs, βarrestin, etc..) and downstream signaling events (cAMP, MAPK, Calcium). The compound with distinct signaling profiles formed clusters of ligands that can also be differentiated based on the cellular impedance responses that they promote. The functional selectivity of ligands acting through a unique GPCR can therefore be assessed using either pathway specific biosensors or global label-free methods thus offering different avenues for drug candidate profiling. Such ligand-biased signaling profiles were observed in both engineered and native cells such as smooth muscle cells and cardiomyocytes indicating that they reflect intrinsic properties of the ligands. Direct assessment of the signaling molecular complexes involved, combined with molecular modeling and virtual docking of the ligands started to reveal the structural determinants of functional selectivity. These studies should provide the basis for the rational design of drugs with predetermined biased signalling profiles and improved therapeutic activities.
Original languageEnglish
Title of host publicationCatecholamine Research in the 21st Century
Subtitle of host publicationAbstracts and Graphical Abstracts, 10th International Catecholamine Symposium, 2012
Number of pages1
ISBN (Print)9780128000441
Publication statusPublished - Dec 2013
Externally publishedYes

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