The role of cyclic AMP and protein kinase A in stimulation of neutrophil migration by endothelins

The role of cAMP and cAMP-dependent protein kinase A (PKA) in endothelin (ET)-stimulated migration of human neutrophils was studied. Endothelins caused an increase in neutrophil migration when they were applied in low (nanomolar) concentrations; stimulation of migration was either predominantly chemokinetic (ET-1) or chemotactic (ET-2, ET-3). All endothelins, at concentrations which gave maximal stimulation of migration, caused an increase of cAMP level. Two inhibitors of adenylate cyclase, MDL-12330A and SQ-22536, completely inhibited migration activated by ET-1, ET-2 or ET-3, indicating that cAMP generation played a decisive role in endothelin-activated migration. The role of PKA in endothelin-activated migration was considered. Two specific antagonists of PKA strongly inhibited endothelin-activated migration. KT-5720, an inhibitor of PKA, also inhibited ET-activated migration, but only when electroporated cells were used. The results suggest that the effect of cAMP on endothelin-activated migration was mediated by PKA.