Biochemical changes in chemoattractantstimulated leukocytes

Transient elevations in intracellular Ca2 , Na2 and cyclic AMP levels, as well as membrane potential changes, occur within seconds after leukocyte exposure to chemoattractants. Chemoattractant binding to receptor activates phospholipase C via guanine nucleotide binding-proteins (G proteins).

The Gi2 and G,, proteins have been found to be the primary G proteins associated with chemoattractant receptors. Upon activation by chemoattractant binding to the receptor, the Gi dissociates into the GTP-bound Ga subunit and 3y subunit complex. The GPy complex regulates phospholipase C[i isoforms in leukocytes. Phospholipase C(3 activation results in the breakdown of phosphatidylinositol 4,5-biphos-phate to form inositol 1,4,5-triphosphate (IP3) and 1,2 s«-diacylglycerol (DAG). The two products of this reaction, IP3 and DAG, activate calcium mobilization (via IP3) and protein kinase C (via DAG). Calcium and protein kinase C appear to be involved in leukocyte cytoskeletal protein modifications. Intracellular free Ca2+ is increased in the lamellipo-dia of migrating neutrophils and affects actin polymerization in chemoattractant-stimulated neutrophils. Other cytoskeletal protein reorganizations may occur via DAG which stimulates protein kinase C to phosphorylate cytoskeletal proteins. Inhibitors of protein kinase C, kinase A and tyrosine kinases inhibit neutrophil chemotaxis to several chemoat-tractants. These findings and others demonstrating the phosphorylation of cytoskeletal proteins in chemoattractant-stimulated neutrophils suggest that cytoskeletal protein phosphorylation is involved in neutrophil chemotaxis.

The coupling and uncoupling of G protein with a chemoattractant receptor may occur via modifications to the G protein and/or the receptor protein. Protein carboxyl methylation may be involved in the modifications of these proteins. Several macrophage membrane proteins are carboxyl methylated by S-adenosylmethionine in an enzymatic reaction that is greatly stimulated by the presence of guanine nucleotides. Macrophage chemotaxis is suppressed by bacterial toxin inhibitors of G proteins and by methylation inhibitors, strongly suggesting that carboxyl methylations may regulate the function of some membrane G proteins.

The receptors for several different chemoattrac-tants have been reported to exist in two affinity states and guanine nucleotides regulate the receptor affinity. One model, which assumes a static population of high- and low-affinity receptors, has proposed that the high-affinity receptors transduce chemotaxis, while the low-affinity receptors transduce oxygen radical production. A second model, which takes into account interconverting receptor states rather than static populations of receptors, postulates that all chemoattractant receptors may participate in all leukocyte responses coupled via G proteins; the responses with low 50% effective doses (ED.,„s) require only a few occupied receptors, whereas the responses with high ED,„s require many receptors to initiate and sustain the response.

Chemoattractant binding to neutrophils and monocytes activates phospholipase A2 and results in arachidonic acid release. Free arachidonic acid is converted by cyclo-oxygenase to thromboxanes and prostaglandins and by lipoxygenation to a variety of hydroxyeicosatetraenoic acids, including Icukotri-enes. Peak intracellular concentrations of these metabolites occur within minutes after chemoattractant stimulation. The precise roles of these products are unknown; however, they may regulate leukocyte responsiveness to chemoattractants and participate in alterations of leukocyte plasma membranes during activation.

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