Larixol is not an inhibitor of Gα i containing G proteins and lacks effect on signaling mediated by human neutrophil expressed formyl peptide receptors.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: eCollection Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford : Elsevier Science
      Original Publication: Oxford, New York [etc.] Paragamon Press.
    • Subject Terms:
      Receptors, Formyl Peptide*/metabolism ; Neutrophils*; Humans ; Signal Transduction ; GTP-Binding Proteins/metabolism
    • Abstract:
      Neutrophils express several G protein-coupled receptors (GPCRs) connected to intracellular Gα i or Gα q containing G proteins for down-stream signaling. To dampen GPCR mediated inflammatory processes, several inhibitors targeting the receptors and/or their down-stream signals, have been developed. Potent and selective inhibitors for Gα q containing G proteins are available, but potent and specific inhibitors of Gα i containing G proteins are lacking. Recently, Larixol, a compound extracted from the root of Euphorbia formosana, was shown to abolish human neutrophil functions induced by N-formyl-methionyl-leucyl-phenylalanine (fMLF), an agonist recognized by formyl peptide receptor 1 (FPR1) which couple to Gα i containing G proteins. The inhibitory effect was suggested to be due to interference with/inhibition of signals transmitted by βγ complexes of the Gα i containing G proteins coupled to FPR1. In this study, we applied Larixol, obtained from two different commercial sources, to determine the receptor- and G protein- selectivity of this compound in human neutrophils. However, our data show that Larixol not only lacks inhibitory effect on neutrophil responses mediated through FPR1, but also on responses mediated through FPR2, a Gα i coupled GPCR closely related to FPR1. Furthermore, Larixol did not display any features as a selective inhibitor of neutrophil responses mediated through the Gα q coupled GPCRs for platelet activating factor and ATP. Hence, our results imply that the inhibitory effects described for the root extract of Euphorbia formosana are not mediated by Larixol and that the search for a selective inhibitor of G protein dependent signals generated by Gα i coupled neutrophil GPCRs must continue.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
    • Contributed Indexing:
      Keywords: G protein inhibitors; G protein-coupled receptors; NADPH-oxidase; Neutrophils; Signaling
    • Accession Number:
      0 (Receptors, Formyl Peptide)
      0 (larixol)
      EC 3.6.1.- (GTP-Binding Proteins)
    • Publication Date:
      Date Created: 20231227 Date Completed: 20240109 Latest Revision: 20240909
    • Publication Date:
      20240909
    • Accession Number:
      10.1016/j.bcp.2023.115995
    • Accession Number:
      38151076