Effect of prenylcysteine analogues on chemoattractant receptor-mediated G protein activation

Kenneth R. McLeish, Eleanor D. Lederer, Jon B. Klein, Jerald L. Hoffman

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

The hypothesis that carboxylmethylationn of γ suunits plays a role in G protein activation was tested by examining the ability of N-acetyl-S-farnesyl-l-cystein (AFC) and its methyl ester (AFC-ME) to inhibit G protein-mediated signalling in intact HL-60 granulocytes and isolated HL-60 plasma membranes. Incubation of HL-60 granulo vytes with AFC of AFC-ME inhibited superoxide release stimulated by fMet-Leu-Phe, but not opsonized bacteria. AFC-ME, but not AFC, inhibited NaF- and PMA-stimulated suproxide release. Addition of AFC to HL-60 membranes inhibited gMet-Leu-Phe-, leukotriene B4 (LTB4) and C5a-stimulated GTPγS binding and GTP hydrolysis more than it inhibited basal guanine nucleotide exchange. AFC-ME inhibited basal- and ligand-stimulated G protein activation with equal potency, but less potently than AFC. AFC also inhibited mastoparan-stimulated GTPγS binding. Binding of fMet-Leu-Phe and LTB4 to HL-60 membranes was completely inhibited by AFC, while AFC-ME inhibited ligand binding by less than 50%. Neither AFC nor AFC-ME inhibited pertussis toxin of cholera toxin-catalysed ADP-ribosylation pf αi. It was concluded that AFC interrupts propagation in G protein-dependent pathways by multiple mechanisms, including inhibition of ligand-receptor interactions, of receptor-G proteins coupling and of guanine nucleotide binding to G proteins. Carboxylmethylation alters the specificity of AFC interuption of signal propagation in intact cells and islated membranes.

Original languageEnglish (US)
Pages (from-to)569-579
Number of pages11
JournalCellular Signalling
Volume6
Issue number5
DOIs
StatePublished - Jul 1994
Externally publishedYes

Keywords

  • carboxylmethylation
  • formyl peptides
  • G proteins
  • HL-60 granulocytes
  • oxidative burst

ASJC Scopus subject areas

  • Cell Biology

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