2. Academic Validation
  3. Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines

Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines

  • FASEB J. 2018 Feb;32(2):862-874. doi: 10.1096/fj.201700555R.
Tonio Pera 1,  Deepak A Deshpande 1,  Michael Ippolito 1,  Bin Wang 1,  Adelina Gavrila 1,  James V Michael 1,  Ajay P Nayak 1,  Eric Tompkins 1,  Eleni Farrell 1,  Wesley K Kroeze 2 3,  Bryan L Roth 2 3 4,  Reynold A Panettieri Jr 5,  Jeffrey L Benovic 6,  Steven S An 7,  Nickolai O Dulin 8,  Raymond B Penn 1
Affiliations

Affiliations

  • 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Center for Translational Medicine, Jane and Leonard Korman Lung Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
  • 2 Department of Pharmacology, University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
  • 3 National Institute of Mental Health Psychoactive Drug Screening Program, School of Medicine, University of North Carolina, Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.
  • 4 Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
  • 5 Rutgers Institute for Translational Medicine and Science, Child Health Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey, USA.
  • 6 Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
  • 7 Department of Environmental Health and Engineering, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA; and.
  • 8 Department of Medicine, Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois, USA.
PMID: 29042451 DOI: 10.1096/fj.201700555R
Abstract

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 protein-coupled receptor OGR1 [ovarian Cancer G protein-coupled receptor 1 ( GPR68)] exhibits diverse signaling events when stimulated by reductions in extracellular pH. We recently demonstrated airway smooth muscle cells transduce multiple signaling events, reflecting a diverse capacity to couple to multiple G proteins. Moreover, we recently discovered that the benzodiazepine lorazepam, more commonly recognized as an agonist of the γ-aminobutyric acid A (GABAA) receptor, can function as an allosteric modulator of OGR1 and, similarly, can promote multiple 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.

Keywords

GPR68; airway smooth muscle; asthma; biased agonism; qualitative signaling.

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