bryostatin-1 and 4-(2-aminoethyl)benzenesulfonylfluoride

Using pharmacologic agents, we explored the mechanism by which a potent neuropeptide, substance P, induces the secretion of histamine from human skin mast cells and compared their effects on substance P-induced histamine release to the secretion activated by anti-IgE. Histamine release from human cutaneous mast cells induced by substance P was inhibited by the Ge-protein inhibitor pertussis toxin that, in turn, did not affect the IgE-mediated secretion. Similarly to anti-IgE, two activators of protein kinase C, tetradecanoylphorbol acetate (TPA) and bryostatin 1, significantly inhibited the substance P-induced response. In contrast, drugs that enhance intracellular levels of cAMP, an inhibitor of protein kinases, genistein, and a protease inhibitor, AEBSF, did not affect substance P-induced histamine secretion, whereas these compounds significantly reduced the response initiated by anti-IgE. Our data demonstrate that substance P activates human cutaneous mast cells by acting on G proteins and protein kinase C. Our results also suggest that the biochemical pathways underlying mast cell activation by substance P and anti-IgE are to a great extent unrelated.

Topics: 1-Methyl-3-isobutylxanthine; Antibodies, Anti-Idiotypic; Bryostatins; Cyclic AMP; Enzyme Activation; Genistein; GTP-Binding Proteins; Histamine Release; Humans; Immunoglobulin E; In Vitro Techniques; Isoflavones; Lactones; Macrolides; Mast Cells; Pertussis Toxin; Protease Inhibitors; Protein Kinase C; Skin; Skin Physiological Phenomena; Substance P; Sulfones; Tetradecanoylphorbol Acetate; Virulence Factors, Bordetella