Detecting ligand functional selectivity at the beta2-adrenergic receptor using a label-free, impedance-based detection method
Wayne Stallaert, Jonas Dorn, Martin Audet & Michel Bouvier
Department of Biochemistry, Institute for Research in Immunology and Cancer and Groupe de Recherche Universitaire sur le Médicament, Université de Montréal, Canada
The discovery that drugs targeting a single G protein-coupled receptor (GPCR) can differentially modulate distinct subsets of the signaling repertoire engaged by the receptor (“functional selectivity”) has created a formidable challenge for drug discovery and development at this important class of therapeutic targets. We show here that cellular impedance measurements provide an integrative assessment of the complexity GPCR signaling elicited by a given ligand-receptor pair. Through a systematic pharmacological analysis, we show that these impedance signatures represent the simultaneous activation of multiple signaling events integrated in real-time and provide evidence of novel signaling and pathway integration of beta2-adrenergic receptor activity. Finally, we present an impedance-based screening procedure and clustering analyses that categorizes compounds based on their distinct impedance signatures and reveal an unexpected level of signaling texture among beta-adrenergic ligands reflecting the signaling pluridimensionality of drugs targeting GPCRs.
|Click [+] for other articles on||The Market Place for Lab Automation & Screening||The Market Place|