Coupling of antagonistic signalling pathways in modulation of neutrophil function.
Modulation of neutrophil activation by catecholamines reflects a fine-tuning by coupling inhibitory and stimulatory receptor pathways. The catecholamine isoproterenol (ISO) binds to beta-adrenergic cell surface receptors and thereby inhibits cell responses such as O2- production stimulated by formyl peptides. However, ISO did not inhibit O2- generation activated by 1 microM ionophore A23187, the protein kinase C activators phorbol ester (PMA, 100 ng/ml) and oleoylacetylglycerol (OAG, 50 microM), and the G-protein activator NaF (40 mM). Furthermore, the overall kinetics of oxidant production in the presence of ISO were unchanged when cells were stimulated with PMA, OAG, A23187, and NaF. These results would imply that neither intracellular calcium, the activation of protein kinase C, nor the activation of G-protein are the primary target of the inhibitory pathway. Accordingly, pertussis toxin did not block PMA or NaF-stimulated superoxide generation. In contrast, formyl peptide-dependent GTPase activity is inhibited by ISO in sonicated cell preparations. Since ISO increases the cAMP concentration in the cell, the possibility is raised that a cAMP-dependent kinase inhibits signal transduction in part by blocking the interaction of this receptor with its G-protein.
Mueller
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Research Institute of Scripps Clinic, Department of Immunology, La Jolla, California 92037.
Sklar
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LA
D000242:Cyclic AMP / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D037342:Pertussis Toxin; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000096:biosynthesis; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D011943:Receptors, Adrenergic, beta; D010566:Virulence Factors, Bordetella; D013481:Superoxides; D000242:Cyclic AMP; D037342:Pertussis Toxin; D011494:Protein Kinases; D011493:Protein Kinase C; D019204:GTP-Binding Proteins; D007545:Isoproterenol