Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines

Tonio Pera, Deepak A. Deshpande, Michael Ippolito, Bin Wang, Adelina Gavrila, James V. Michael, Ajay P. Nayak, Eric Tompkins, Eleni Farrell, Wesley K. Kroeze, Bryan L. Roth, Reynold A. Panettieri, Jeffrey L. Benovic, Steven An, Nickolai O. Dulin, Raymond B. Penn

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)862-874
Number of pages13
JournalFASEB Journal
Volume32
Issue number2
DOIs
StatePublished - Feb 1 2018

Fingerprint

GABA-A Receptors
Benzodiazepines
Protons
GTP-Binding Proteins
Ligands
Aminobutyrates
Lorazepam
G-Protein-Coupled Receptors
Ovarian Neoplasms
Pharmacology
Conformations

Keywords

  • Airway smooth muscle
  • Asthma
  • Biased agonism
  • GPR68
  • Qualitative signaling

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Pera, T., Deshpande, D. A., Ippolito, M., Wang, B., Gavrila, A., Michael, J. V., ... Penn, R. B. (2018). Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines. FASEB Journal, 32(2), 862-874. https://doi.org/10.1096/fj.201700555R

Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines. / Pera, Tonio; Deshpande, Deepak A.; Ippolito, Michael; Wang, Bin; Gavrila, Adelina; Michael, James V.; Nayak, Ajay P.; Tompkins, Eric; Farrell, Eleni; Kroeze, Wesley K.; Roth, Bryan L.; Panettieri, Reynold A.; Benovic, Jeffrey L.; An, Steven; Dulin, Nickolai O.; Penn, Raymond B.

In: FASEB Journal, Vol. 32, No. 2, 01.02.2018, p. 862-874.

Research output: Contribution to journalArticle

Pera, T, Deshpande, DA, Ippolito, M, Wang, B, Gavrila, A, Michael, JV, Nayak, AP, Tompkins, E, Farrell, E, Kroeze, WK, Roth, BL, Panettieri, RA, Benovic, JL, An, S, Dulin, NO & Penn, RB 2018, 'Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines', FASEB Journal, vol. 32, no. 2, pp. 862-874. https://doi.org/10.1096/fj.201700555R
Pera T, Deshpande DA, Ippolito M, Wang B, Gavrila A, Michael JV et al. Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines. FASEB Journal. 2018 Feb 1;32(2):862-874. https://doi.org/10.1096/fj.201700555R
Pera, Tonio ; Deshpande, Deepak A. ; Ippolito, Michael ; Wang, Bin ; Gavrila, Adelina ; Michael, James V. ; Nayak, Ajay P. ; Tompkins, Eric ; Farrell, Eleni ; Kroeze, Wesley K. ; Roth, Bryan L. ; Panettieri, Reynold A. ; Benovic, Jeffrey L. ; An, Steven ; Dulin, Nickolai O. ; Penn, Raymond B. / Biased signaling of the proton-sensing receptor OGR1 by benzodiazepines. In: FASEB Journal. 2018 ; Vol. 32, No. 2. pp. 862-874.
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AU - Roth, Bryan L.

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