INFLUENCE OF ALPHA-HELICITY, AMPHIPATHICITY AND D-AMINO-ACID INCORPORATION ON THE PEPTIDE-INDUCED MAST-CELL ACTIVATION

Mast cell activation by polycationic substances is believed to result from a direct activation of G protein alpha subunits and it was sugges ted that the adaption of amphipathic, alpha-helical conformations woul d allow the peptide to reach the cytosolic compartment to interact wit h G proteins (Mousli et al., 1994, Immunopharmacology 27, 1, for revie w). We investigated the histamine-releasing activity of model peptides as well as analogues of magainin 2 amide and neuropeptide Y with diff erent amphipathicities and alpha-helix content on rat peritoneal mast cells. Amphipathic helicity is not a prerequisite for mast cell activa tion. Moreover, non-helical magainin peptides with high histamine-rele asing activity were less active in the liberation of carboxyfluorescei ne from negatively charged liposomes, indicating that peptide-induced mast cell activation and peptide-induced membrane perturbation do not correlate. In contrast to the negligible influence of the secondary st ructure, amino acid configuration may exert a striking influence on pe ptide-induced mast cell activation. Thus histamine-release by substanc e P was markedly impaired when the L-amino acids in the positively cha rged N-terminal region were replaced by D-amino acids, with [D-Arg(1)] substance P being the most inactive substance P diastereoisomer.