We have previously established that the binding of chemotactic factors to their receptors on the plasma membrane of neutrophils leads, among other things, to a graded displacement of calcium from membraneous stores and to an increase in membrane permeability to Ca2 ion and Na ion. A role for arachidonic acid or its metabolites has also been strongly suggested in the sequence of steps leading to the plasma membrane permeability changes. The net results of these two events is to evaluate the level of exchangeable intracellular calcium which has been shown to be important, probably as a second messenger, in most if not all neutrophil functions. We wish now to identify, map, and sequence the events that lead to and those that regulate the stimulus induced increase in the level of exchangeable Ca2 ion. To this end, we plan to further define the effect of neutrophil specific stimuli, such as chemotactic factors and secretagogues, on intracellular Ca2 ion distribution, to examine the relationship between stimulated membrane lipid metabolism, particularly phosphatidyl inositol, and the mechanism of cation gating, and to investigate the role of cyclic nucleotides and of the plasma membrane bound Ca2 ion ATPase in the regulation of the intracellular levels of exchangeable calcium. Furthermore, we intend to investigate directly to the interrelationship between Ca2 ion transport and arachidonic acid metabolism and to extend these studies to include Na ion movements. The interrelationships between Ca2 ion transport and the movements of Na ion, K ion and H ion will also be studied. The possible involvement of calmodulin in the mediation of the various calcium activated events, such as protein phosphorylation, that ultimately allow the expression of the various neutrophil functions will be investigated.
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