Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines

GPCRs have diverse signaling capabilities, based on their ability to assume various conformations. Moreover, it is now appreciated that certain ligands can promote distinct receptor conformations and thereby bias signaling toward a specific pathway to differentially affect cell function. The recently deorphanized G proteincoupled receptor OGR1 [ovarian cancer G protein-coupled receptor 1 (GPR68)] exhibits diverse signaling events whenstimulated by reductions in extracellularpH.We recentlydemonstratedairway smoothmuscle cells transduce multiple signaling events, reflecting a diverse capacity to couple to multiple G proteins. Moreover, we recently discoveredthat thebenzodiazepine lorazepam,more commonly recognizedas anagonist of theg-aminobutyric acid A(GABAA) receptor, canfunctionas anallostericmodulator ofOGR1and, similarly, canpromotemultiple signaling events. In this study, we demonstrated that different benzodiazepines exhibit a range of biases for OGR1, with sulazepam selectively activating the canonical Gs of the G protein signaling pathway, in heterologous expression systems, as well as in several primary cell types. These findings highlight the potential power of biased ligand pharmacology for manipulating receptor signaling qualitatively, to preferentially activate pathways that are therapeutically beneficial.-Pera, T.,Deshpande,D. A., Ippolito, M.,Wang, B.,Gavrila,A., Michael, J. V.,Nayak, A. P., Tompkins,E.,Farrell,E.,Kroeze,W.K., Roth,B.L., Panettieri, R. A. Jr.,Benovic, J.L.,An, S. S.,Dulin,N.O.,Penn,R. B. Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines. FASEB J. 32, 862-874 (2018). www.fasebj.org.