The mechanism of inhibition of alkylamines on the mast-cell peptidergic pathway.
GTP-binding proteins are known to play an important role in controlling mast-cell exocytosis and are described as the primary targets of peptidic mast-cell histamine releasers. The mechanism of inhibition of the mast-cell peptidergic pathway by alkylamines, which are selective inhibitors of this pathway, was investigated using intact or permeabilized rat peritoneal mast cells. Histamine release induced by GTP gamma S and by mastoparan (a venom peptide activating G proteins) was inhibited by pretreating mast cells with 0.1 to 3 micrograms/ml of a mixture of benzalkonium chloride containing in majority a twelve-carbon-atom aliphatic chain (BAC(C approximately 12)). Pure benzalkonium chloride, with a fourteen-carbon-atom aliphatic chain (BAC (C14)), at 5 to 10 microM also inhibited histamine release induced by GTP gamma S and mastoparan. The dose-response curve of mastoparan-induced histamine release from intact mast cells was shifted to the right by various concentrations of BAC (C14). Similar results were obtained with another alkylamine differing from BAC (C14) by the absence of the benzene ring, tetradecyltrimethylammonium bromide, TAB (C14). This illustrates that the presence of the phenyl radical is not required for the inhibitory effect of benzalkonium chloride. BAC (C approximately 12) and BAC (C14) inhibited the generation of inositol polyphosphates induced by GTP gamma S. BAC (C approximately 12) and TAB (C14) inhibited the mastoparan-stimulated GTPase activity from mast-cell Gi-like proteins. These results suggest that alkylamines exert selectively their inhibitory effect via an interaction with mast-cell Gi-like proteins coupled to phospholipase C, i.e., at an early stage in the stimulus-secretion coupling process.
Fischer
T
T
Laboratoire de Neuroimmunopharmacologie, Université Louis Pasteur-Strasbourg I, Illkirch, France.
Bronner
C
C
Landry
Y
Y
Mousli
M
M
D001548:Benzalkonium Compounds / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000037:antagonists & inhibitors; D006633:Histamine Antagonists / Q000494:pharmacology*; D007295:Inositol Phosphates / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D010452:Peptide Biosynthesis; D010455:Peptides; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D050337:Trimethyl Ammonium Compounds; D014862:Wasp Venoms / Q000037:antagonists & inhibitors
D001548:Benzalkonium Compounds; D006633:Histamine Antagonists; D007295:Inositol Phosphates; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D000644:Quaternary Ammonium Compounds; D050337:Trimethyl Ammonium Compounds; D014862:Wasp Venoms; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C037500:mastoparan; D019204:GTP-Binding Proteins; C009410:tetradecyltrimethylammonium