Subtle differences between human and rabbit neutrophil receptors shown by the secretagogue activity of constrained formyl peptides.
Stereochemically constrained extended beta-antiparallel and folded beta-turn analogs of the chemotactic agent N-formyl-Met-Leu-Phe-OH were tested for their ability to induce the release of beta-glucuronidase from human and rabbit neutrophils. Selected biologically active peptides were further examined for their capacity to inhibit the binding of f-Met-Leu-[3H]Phe to whole human neutrophils at 4 degrees C. The results suggest that Dpg2 analogs with the extended backbone are significantly more potent in human peripheral blood neutrophils than the folded beta-turn analogs. Surprisingly, in rabbit peritoneal neutrophils, the extended Dpg2 analog appears to be marginally less active than the flexible parent peptide and the folded Ac6c2 analog. In human neutrophils, the secretagogue activity increases in the following order with alteration in the C-terminal functions: -CONH2 < -COOMe < -COOH << -COOBzl. However, this order of potency differs from that observed for the rabbit formyl peptide receptor (-COOH < -COOMe < -CONH2 << -COOBzl). In human neutrophils, the peptides' ability to compete for the receptor binding site of f-Met-Leu-[3H]Phe correlates well with their secretagogue potency. The results provide convincing evidence for the existence of subtle differences between human peripheral blood neutrophils and rabbit peritoneal neutrophils with regard to ligand-receptor interactions of constrained chemotactic peptides. What is new and novel in this report is that constrained peptides can distinguish between the rabbit and human chemotactic peptide receptors which have so far been believed to have similar response to secretagogue agents. The data emphasize that directly relating the secretagogue activity observed in rabbit neutrophils to that observed in human neutrophils may not be unequivocal.
Dentino
A R
AR
Division of Periodontics, School of Dentistry, Marquette University, Milwaukee, Wisconsin 53201, USA.
Raj
P A
PA
De Nardin
E
E
D000818:Animals; D005966:Glucuronidase / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011817:Rabbits; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism*; D013696:Temperature
D008024:Ligands; D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D018000:Receptors, Peptide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D005966:Glucuronidase