Abstract
The binding of ligands to N-formyl peptide chemoattractant receptors in human neutrophils results in a rapid association of these receptors with a cytoskeletal fraction and a specific activation and release of Gi2 alpha-subunits from this fraction. In the present study we could show that pretreating neutrophils with GDPbetaS prevented the fMet-Leu-Phe-induced association of its receptor with a cytoskeletal fraction and also blocked the release of Gi2 alpha-subunits from the same cytoskeletal fraction. In contrast, direct activation of Gi2 proteins by addition of GTPgammaS or AlF4- not only caused a release of Gi2 alpha-subunits from the cytoskeleton but also an association of formyl peptide receptors with the cytoskeleton. The receptor for complement fragment 5a, which transduces its signaling through the same Gi2 protein, triggers both a release of Gi2 alpha-subunits from the cytoskeleton fraction and, of even greater interest, an association between formyl peptide receptors and the cytoskeleton. The close relationship between the activation and release of Gi2 alpha-subunits from the cytoskeleton and the association of formyl peptide receptors with the cytoskeleton might, however, not be a matter of protein-protein exchange, since the increased binding of formyl peptide receptors to the cytoskeleton occurs more rapidly than the release of Gi2 alpha-subunits from the cytoskeleton. The present findings suggest a possible mechanism for the initiation of formyl peptide receptor desensitization during neutrophil locomotion.
Highlights
Human neutrophils are phagocytic cells specialized in the destruction of invading microorganisms
Considering the neutrophil FPR, it has previously been suggested that binding to the cytoskeleton is an important step in the desensitization of this receptor to chemotactic peptides (Jesaitis et al, 1984; Jesaitis et al, 1986)
Our original interpretation is supported by the present finding that the association between the FPR and the cytoskeleton was inhibited in GDPS-treated neutrophils, as shown by immunoblot analysis (Fig. 1A)
Summary
Human neutrophils are phagocytic cells specialized in the destruction of invading microorganisms To perform this important role in host defense, these cells emigrate from the blood vessels to the sites of infection. The neutrophil receptor for N-formylated peptides (FPR) is one of the most thoroughly studied chemoattractant receptors (for review, see Murphy, 1994). This receptor is a glycosylated protein with an apparent molecular mass of 50 –70 kDa, as estimated by photoaffinity labeling (Tardif et al, 1993; Sengeløv et al, 1994). To be able to move in a chemotactic gradient, motile cells like the human neutrophil must respond to changes in the concentration of one or probably several stimuli In part, this is achieved by an adaptive process that results in a blunted response despite the permanent presence of agonists. Such segregation could well be a consequence of the N-formyl-L-methionyl-L-
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