THE MECHANISM OF INHIBITION OF ALKYLAMINES ON THE MAST-CELL PEPTIDERGIC PATHWAY

GTP-binding proteins are known to play an important role in controllin g mast-cell exocytosis and are described as the primary targets of pep tidic mast-cell histamine releasers. The mechanism of inhibition of th e mast-cell peptidergic pathway by alkylamines, which are selective in hibitors of this pathway, was investigated using intact or permeabiliz ed rat peritoneal mast cells. Histamine release induced by GTPgammaS a nd by mastoparan (a venom peptide activating G proteins) was inhibited by pretreating mast cells with 0.1 to 3 mug/ml of a mixture of benzal konium chloride containing in majority a twelve-carbon-atom aliphatic chain (BAC (C(approximately 12)). Pure benzalkonium chloride, with a f ourteen-carbon-atom aliphatic chain (BAC (C-14)), at 5 to 10 muM also inhibited histamine release induced by GTPgammaS and mastoparan. The d ose-response curve of mastoparan-induced histamine release from intact mast cells was shifted to the right by various concentrations of BAC (C-14). Similar results were obtained with another alkylamine differin g from BAC (C-14) by the absence of the benzene ring, tetradecyltrimet hylammonium bromide, TAB (C-14). This illustrates that the presence of the phenyl radical is not required for the inhibitory effect of benza lkonium chloride. BAC (C approximately 12) and BAC (C-14) inhibited th e generation of inositol polyphosphates induced by GTPgammaS. BAC (C a pproximately 12) and TAB (C-14) inhibited the mastoparan-stimulated GT Pase activity from mast-cell G(i)-like proteins. These results suggest that alkylamines exert selectively their inhibitory effect via an int eraction with mast-cell G(i)-like proteins coupled to phospholipase C, i.e., at an early stage in the stimulus-secretion coupling process.