The J774 murine macrophage cells possess a P2-adrenergic receptor coupled to adenylate cyclase, which can be regulated by homologous desensitization. Stimulation of protein kinase C by phorbol esters or oleoyl acetyl glycerol potentiates two-to-threefold the isoproterenol-induced cyclic AMP accumulation. These promoters act at a post-receptor level, since the number and affinity of the P-adrenergic receptors, measured by use of the hydrophilic ligand [3H]CGP-12 177, are not modified. In addition, the effect of cholera toxin is similarly increased and pretreatment of the cells with pertussis toxin prevents the action of phorbol esters. On the other hand, these promoters are ineffective on isoproterenol-induced desensitization and the rates of receptor segregation and recovery remain unchanged. Therefore, protein kinase C modulates the isoproterenol-stimulated adenylate cyclase, whereas it is inactive on the homologous desensitization process.The phorbol esters are well-known tumor promoters which stimulate the CaZ + and phospholipid-dependent protein kinase C. They substitute for diacylglycerol, which is the natural activator of protein kinase C and is produced from hormone and growth-factor-induced turnover of polyphosphoinositides [l].Recently, it has been demonstrated that the phorbol esters can interfere with the hormone-mediated adenylate cyclase activation. The data concerning p-adrenergic-mediated stimulation depend on the cell type studied. Thus, in some cells the tumor promoters induce P-adrenergic desensitization [2 -161, while in others they potentiate the response to isoproterenol [17-241. In addition, in cell-free systems protein kinase C either increases [20, 251 or decreases [8, 261 the basal and stimulated adenylate cyclase. The molecular mechanisms of these effects are actively investigated. The data demonstrate that the number and affinity of P-adrenergic receptors remain unchanged [5,9,13, 18, 20, 221 has demonstrated that the catalytic unit of adenylate cyclase is phosphorylated in vivo by phorbol esters [29].On the other hand, few studies have investigated the action of protein kinase C on the homologous desensitization of padrenergic receptors [16, 241. Recent work has demonstrated that this is a cyclic-AMP-independent phenomenon, related to the phosphorylation of B-receptors by a specific kinase (review in [30]). The aim of our study was to investigate the effect of phorbol esters on the two types of the action of j-agonists: the stimulation of cyclic AMP production and the homologous desensitization. We took advantage of the availability of the hydrophilic P-adrenergic ligand, [3H]CGP-12 177, which is membrane-impermeant and allows for the investigation of surface receptors on intact cells [31].We used in this study a continuous cell line of murine macrophages, 5774 [32, 331, which is sensitive both to cyclic AMP derivatives [34, 351 and to phorbol esters [36].Our data demonstrate that (a) protein kinase C activation by phorbol esters or oleoyl acetyl glycerol potentiates the isopr...