Cross-desensitization of receptors for peptide chemoattractants. Characterization of a new form of leukocyte regulation.
The formylpeptide (fMLP) and C5a chemoattractants were previously shown to cross-desensitize each other's ability to mobilize Ca2+ in leukocytes but not to affect nonchemoattractant Ca(2+)-mobilizing receptors, and vice versa. Our data show that all receptors studied underwent homologous desensitization. Interestingly, peptide chemoattractants (fMLP, C5a, and IL-8) desensitized each other's Ca(2+)-mobilizing responses, but had no effect on a Ca(2+)-mobilizing purinergic receptor. Lipid chemoattractant receptors (PAF and leukotriene B4) were also desensitized by peptide chemoattractants but not vice versa. In the presence of cytochalasin B, only fMLP and C5a caused the activation of phospholipase D in intact leukocytes and enhanced desensitization of IL-8 and C5a but not fMLP receptors. To measure receptor/G protein interactions, agonist-stimulated GTP gamma S binding to leukocyte membranes was measured. Whereas all peptide receptors underwent homologous desensitization, C5a and IL-8, but not fMLP, receptors were cross-desensitized by other peptide chemoattractants. Furthermore, PMA caused inhibition of C5a- and IL-8- but not fMLP-stimulated GTP gamma S binding. These data suggest that in addition to homologous desensitization, peptide chemoattractant receptors cross-desensitize one another by at least two processes. One can be detected at the level of receptor/G-protein interaction and possibly involves receptor phosphorylation by protein kinase C. The fMLP receptor is resistant to this process. The second process is distal to receptor/G-protein interaction and utilizes an undefined pathway to cross-desensitize the Ca2+ mobilization response to all peptide chemoattractants. We propose that receptor cross-desensitization in leukocytes is orchestrated at several levels by mechanisms with selectivity for types of chemoattractant receptors.
Tomhave
E D
ED
Department of Medicine, Duke University Medical Center, Durham, NC 27710.
Richardson
R M
RM
Didsbury
J R
JR
Menard
L
L
Snyderman
R
R
Ali
H
H
D000255:Adenosine Triphosphate / Q000378:metabolism; D000470:Alkaloids / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D002634:Chemotaxis, Leukocyte; D003571:Cytochalasin B / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000378:metabolism*; D010739:Phospholipase D / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000378:metabolism*; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000378:metabolism*; D018000:Receptors, Peptide / Q000378:metabolism*; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000470:Alkaloids; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D018000:Receptors, Peptide; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D003571:Cytochalasin B; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D010739:Phospholipase D; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium