Further studies on the structural requirements for polypeptide-mediated histamine release from rat mast cells

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Abstract
Structure-activity studies were performed on a series of naturally occurring and tailor-made polypeptides, by measurement of ability to induce selective histamine release from normal rat peritoneal mast cells in vitro. Compounds investigated included ACTH and melittin derivatives, mast-cell-degranulating peptide from bee venom, polymyxin B, bradykinin and various synthetic poly(amino acids) and short-chain peptides. A cluster of 4 basic residues (lysine or arginine) was optimal for histamine release by corticotropin and melittin polypeptides, provided that the C-terminal carboxyl group was substituted (e.g., by amidation). The presence of a free C-terminal carboxyl group of nearby dicarboxylic acid residues led to a considerable diminution in histamine-releasing activity. Polypeptides comprised essentially of acidic amino acids were inactive. Synthetic peptides comprising a particular sequence within the Fc region of human immunoglobulin E, the immunoglobulin class particularly involved in mediation of allergic reactions of the immediate type, would probably possess potent histamine-releasing activity when similarly made to react with normal rat mast cells. The further study of such a structure should clarify the molecular basis of allergen-antibody triggering of mast cells.