Amyloid-β peptide, substance P, and bombesin bind to the serpin-enzyme complex receptor

During the formation of an inhibitory complex with neutrophil elastase, α₁ antitrypsin (α₁ AT) undergoes a structural rearrangement and the resulting α₁ AT-elastase complex becomes endowed with chemoattractant activities, mediates an increase in synthesis of α₁ AT, and is rapidly cleared from the circulation. In previous studies we have provided evidence that these biological activities involve the recognition of a conformation-specific domain in the α₁ AT molecule by a cell surface receptor on human hepatoma HepG₂ cells and human monocytes. The receptor has been termed the serpin-enzyme complex (SEC) receptor because it also recognizes complexes of serpins antithrombin III, α₁ anti-chymotrypsin, and C1 inhibitor with their cognate enzymes. Because a pentapeptide domain of α₁ AT (amino acids 370-374, Phe-Val-Phe-Leu-Met) is sufficient for binding to the SEC receptor and the sequence of this domain is remarkably similar to those of substance P, several other tachykinins, bombesin, and the amyloid-β peptide, we have examined the possibility that these other ligands bind to the SEC receptor. The results indicate that substance P, several other tachykinins, and bombesin compete for binding to, and cross-linking of, the SEC receptor. The SEC receptor is distinct from the substance P receptor by several criteria. There is no substance P receptor mRNA in HepG2 cells; the SEC receptor is present in much higher density on receptor-bearing cells and binds its ligands at lower affinity than the substance P receptor; the SEC receptor is much less restricted in the specificity with which it recognizes ligand; ligands for the SEC receptor including peptide 105Y (based on α₁AT sequence 359-374), α₁ AT-protease complexes, and bombesin do not compete for binding of substance P to a stable transfected cell line expressing the substance P receptor. Finally, we show here that the amyloid-β peptide competes for binding to the SEC receptor but does not bind to the substance P receptor, therein raising the possibility that the SEC receptor is involved in certain biological activities, including the recently described neurotrophic and neurotoxic effects ascribed to the amyloid-β peptide.