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 0,production stimulated by formyl peptides. However, IS0 did not inhibit 0,generation activated by 1 pM ionophore A23 187, the protein kinase C activators phorbol ester (PMA, 100 ng/ml) and oleoylacetylglycerol (OAG, 50 pM), and the G-protein activator N a F (40 mM). Furthermore, the overall kinetics of oxidant production in the presence of IS0 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 NaFstimulated superoxide generation. In contrast, formyl peptide-dependent GTPase activity is inhibited by IS0 in sonicated cell preparations. Since IS0 increases the CAMP concentration in the cell, the possibility is raised that a cA M P-dependent kinase inhibits signal transduction in part by blocking the interaction of this receptor with its G-protein.