Stimulus-secretion coupling in the human neutrophil: the role of phosphatidic acid and oxidized fatty acids in the translocation of calcium.
Neutrophils, stimulated via their surface receptors by ligands such as f-Met-Leu-Phe or immune complexes, release membrane calcium from intracellular stores and accumulate calcium from the extracellular medium. Both mechanisms provide for a rise in the intracellular concentration of free calcium which appears to be required for later responses of the cell: release of lysosomal enzymes and the generation of superoxide anion as neutrophils undergo an aggregation response. Exogenous ionophores, such as A23187 and PGBx, which move calcium bidirectionally across lipid bilayers, bypass the ligand-receptor step, thereby providing the necessary rise in intracellular calcium. In the course of the remodeling of membrane lipids--within 5 sec after their exposure to a stimulus--neutrophils generate phosphatidic acid, at least in part at the expense of phosphatidyl inositol. Because phosphatidic acid is the only phospholipid whose action in model membranes mimics the action of exogenous ionophores (as it is formed early enough and in sufficient quantities to account for uptake of extracellular calcium), we propose phosphatidic acid as a promising candidate for the role of endogenous ionophore. This ionophoretic action may serve to amplify signals launched by primary changes at the plasma membrane from whence calcium is mobilized during stimulus-secretion coupling. The release of oxidation products of arachidonic acid, be it via the cyclo-oxygenase or lipoxygenase pathway, is a concomitant of neutrophil activation. Indeed, the pathways by which oxidative products of arachidonate are formed may also be influenced by stimulus-specific changes in membrane phospholipids, not the least interesting of which is the generation of phosphatidic acid.
D001091:Arachidonate Lipoxygenases; D001095:Arachidonic Acids / Q000097:blood*; D001693:Biological Transport, Active; D002118:Calcium / Q000097:blood*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002449:Cell Aggregation / Q000187:drug effects; D005966:Glucuronidase / Q000097:blood; D006801:Humans; D007700:Kinetics; D008084:Lipoxygenase / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010712:Phosphatidic Acids / Q000097:blood*; D013481:Superoxides / Q000097:blood
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D010712:Phosphatidic Acids; D013481:Superoxides; D001091:Arachidonate Lipoxygenases; D008084:Lipoxygenase; D005966:Glucuronidase; D002118:Calcium