Amphotericin B alters the affinity and functional activity of the oligopeptide chemotactic factor receptor on human polymorphonuclear leukocytes.
Leukocyte chemotaxis is initiated by the binding of chemotactic factors to specific, high-affinity receptors. Amphotericin B, a polyene antibiotic that binds to membrane cholesterol, inhibits human neutrophil (PMN) chemotaxis. We examined the effects of this drug on PMN functions mediated by the oligopeptide chemotactic factor receptor. The antibiotic irreversibly inhibited chemotaxis and depressed the binding of the radiolabeled chemoattractant, fMet-Leu-[3H]Phe, to its receptor without affecting the receptor's specificity. The drug lowered the binding affinity of the receptor by up to fivefold and slightly increased its number. Doses of amphotericin B that depressed receptor affinity and inhibited chemotaxis did not diminish lysosomal enzyme secretion or superoxide anion production. Nystatin, a less potent polyene antibiotic, also diminished chemotactic factor binding, but to a lesser degree than amphotericin B did. A chemically unrelated antifungal agent had no effect on either binding or chemotaxis. Thus, pharmacologic manipulation can alter the affinity of the chemotactic factor receptor on human PMN; this alteration is associated with a change in receptor function. The data suggest that receptor affinity regulates or at least reflects its functional state, and that the transduction mechanisms for various biologic responses mediated by the chemoattractant receptor are heterogeneous. By pharmacologic alterations of receptor affinity, one may be able to modulate specific biologic responses elicited by chemoattractant receptor-ligand interactions.
D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006801:Humans; D008247:Lysosomes / Q000201:enzymology; D008563:Membrane Lipids / Q000502:physiology; D008715:Methionine / Q000031:analogs & derivatives*; D009239:N-Formylmethionine / Q000031:analogs & derivatives* / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D009842:Oligopeptides / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000187:drug effects*; D044042:Receptors, Formyl Peptide; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism
D000935:Antifungal Agents; D008563:Membrane Lipids; D009842:Oligopeptides; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D013481:Superoxides; D009239:N-Formylmethionine; D009240:N-Formylmethionine Leucyl-Phenylalanine; D000666:Amphotericin B; D008715:Methionine