Oxysterols act as promiscuous ligands of class-A GPCRs: In silico molecular modeling and in vitro validation

Cristina Sensi, Simona Daniele, Chiara Parravicini, Elisa Zappelli, Vincenzo Russo, Maria L. Trincavelli, Claudia Martini, Maria P. Abbracchio, Ivano Eberini

Research output: Contribution to journalArticle

Abstract

According to classical pharmacology, each neurotransmitter/hormonal receptor, including GPCRs, is exclusively activated by highly specific ligands. However, recent evidence challenges this dogma. Oxysterols are produced at inflammatory sites and can surprisingly potently activate the Epstein Barr virus induced gene receptor-2 (EBI2), a GPCR involved in adaptive immune responses. Similarly, oxysterols promiscuously operate CXCR2, a chemokine receptor participating to immune reactions and cancer development. Both EBI2 and CXCR2 are phylogenetically related to GPR17, another GPCR implicated in inflammatory/immune neurodegenerative events. Here, we used an integrated approach combining comparative modeling, molecular docking and in vitro experiments to investigate their potential interactions with oxysterols. All three receptors share the binding site to allocate oxysterols with different local arrangements, higher sensitivity to specific oxysterols and different activation thresholds. Such differences may dictate the diverse biological effects induced by oxysterols, depending on production site, concentration, specific spatiotemporal features and receptor expression on targeted cells. Thus, EBI2, CXCR2 and GPR17 are promiscuously operated by oxysterols making this class of ligands a '. fil rouge' linking oxidative stress, inflammation and neurodegeneration. Such a transversal role may represent a conserved, "unspecific" (but selective) signaling mode, by which emergency molecules activate multiple receptors involved in inflammatory/immune responses.

Original languageEnglish
Pages (from-to)2614-2620
Number of pages7
JournalCellular Signalling
Volume26
Issue number12
DOIs
Publication statusPublished - Dec 1 2014

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Keywords

  • Cell signaling
  • Cholesterol
  • G proteins
  • Molecular recognition
  • Oxysterols
  • Receptors/seven transmembrane domain

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Sensi, C., Daniele, S., Parravicini, C., Zappelli, E., Russo, V., Trincavelli, M. L., Martini, C., Abbracchio, M. P., & Eberini, I. (2014). Oxysterols act as promiscuous ligands of class-A GPCRs: In silico molecular modeling and in vitro validation. Cellular Signalling, 26(12), 2614-2620. https://doi.org/10.1016/j.cellsig.2014.08.003