The mechanism of basophil histamine release induced by pepstatin A.
Pepstatin A, a natural pentapeptide isolated from cultures of actinomycetes, induced histamine secretion from human basophils in the concentration range of 3 X 10(-7) to 10(-4) M. The characteristics of this reaction were similar to those of f-met-peptide-induced histamine release: pepstatin A-induced release required Ca2+, and the release reaction was complete within 2 min at 22 or 37 degrees C but did not occur at 4 degrees C. There was excellent correlation (r = 0.93; p less than 0.001) between the maximal histamine release induced by pepstatin A and f-met-peptide, but there was no relationship to the capacity of basophils to release with anti-IgE (r = -0.03) or the Ca2+ ionophore A23187 (r = -0.22). Release by pepstatin A was reversibly inhibited by two nonreleasing analogs of f-met-peptide, CBZ-Phe-Met and BOC-Met-Leu-Phe. BOC-Met-Leu-Phe competitively inhibited the effect of both f-met-peptide and pepstatin A on histamine release from basophils. The dissociation constant (Kd) for the BOC-Met-Leu-Phe-receptor complex in both conditions was approximately 10(-6) M. Furthermore, there was complete cross-desensitization between pepstatin A and f-met-peptide, whereas cells desensitized to pepstatin A released normally with anti-IgE and vice versa. A variety of pharmacologic agents had similar effects on both pepstatin A- and f-met-peptide-induced release (e.g., slight inhibition with cyclic AMP-active agents, no enhancement with D2O, and marked enhancement with cytochalasin B). We suggest that the natural pentapeptide pepstatin A induces histamine release from human basophils by activating a cell surface receptor(s) also activated by the synthetic tripeptide f-met-peptide.
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000293:Adolescent; D000328:Adult; D000527:Alprostadil; D001491:Basophils / Q000276:immunology* / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology; D003429:Cross Reactions; D003888:Desensitization, Immunologic; D004306:Dose-Response Relationship, Immunologic; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D008875:Middle Aged; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology*; D010436:Pepstatins / Q000494:pharmacology*; D011458:Prostaglandins E / Q000494:pharmacology
D009842:Oligopeptides; D010436:Pepstatins; D011458:Prostaglandins E; C014195:Streptomyces pepsin inhibitor; D009240:N-Formylmethionine Leucyl-Phenylalanine; D003994:Bucladesine; D000527:Alprostadil; D015056:1-Methyl-3-isobutylxanthine; C031375:pepstatin