Ligand-receptor dynamics and signal amplification in the neutrophil.
Intact neutrophils appear to exhibit interconverting formyl peptide receptor states. The first may be active in transduction and has a dissociation half-time of less than 10 sec. The second appears to be inactive and has a dissociation half-time of approximately 2 min. Neutrophil signals and responses are transient following "pulse" stimulation (when the stimulus is presented and then rapidly removed). The responses decay to baseline following a latency period comparable to the lifetime of the activated receptor. These results are consistent with the notion of transient interconverting receptor states and are discussed in terms of the biochemistry and amplification of the cell activation pathways. We examined the effect of guanine nucleotides on ligand-receptor dynamics at 37 degrees C in neutrophils permeabilized with digitonin, using continuous fluorometric measurements. The permeabilized cells exhibit a single class of slowly-dissociating receptor with a half-time similar to the inactive state. When guanine nucleotide is added, the receptors dissociate with a half-time similar to the first state. The effect of guanine nucleotide is inhibited by Ca++ concentrations above 10 microM. When receptors in permeabilized cells are ADP-ribosylated in the presence of pertussis toxin, the rapidly dissociating state is detected. These results suggest that the dynamics of ligand-receptor interaction under physiological conditions are controlled by a pertussis-toxin-sensitive guanine-nucleotide-binding protein. Guanine nucleotide regulates interconverting states of the formyl peptide receptor and mimics the dynamic states of the receptor observed in the intact cell during stimulation. A model which accounts for these data is described.
D002118:Calcium / Q000494:pharmacology; D005454:Fluorescence Polarization; D019204:GTP-Binding Proteins / Q000378:metabolism; D006150:Guanine Nucleotides / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D009504:Neutrophils / Q000502:physiology*; D009842:Oligopeptides / Q000378:metabolism*; D037342:Pertussis Toxin; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000378:metabolism*; D012984:Software; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D006150:Guanine Nucleotides; D009842:Oligopeptides; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D010566:Virulence Factors, Bordetella; C021642:F-chemotactic peptide; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D002118:Calcium