Receptors and Intracellular Signaling in Human Neutrophils

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Abstract
Adherence, chemotaxis, phagocytosis, and responses to cytokines are mediated by distinct classes of cell surface receptors in human neutrophils. Intracellular signaling by these different receptors is a subject of active investigation. Observation of single neutrophils adherent to surfaces reveals the presence of spontaneous oscillations of cytosolic-free calcium, [Ca2+]i, generated by mechanisms that are presently unknown. Chemoattractant receptor activation via a specific G-regulatory protein activates a plasma membrane phospholipase C and generates diacylglycerol and inositol(1,4,5)triphosphate. DG activates C kinase(s). Ins(1,4,5)P3 releases Ca2+ from a specific intracellular organelle, the calciosome. Calciosomes resemble sarcoplasmic reticulum: they contain a Ca2(+)-ATPase and a high capacity/low affinity calcium-binding, calsequestrin-like protein. Chemoattractant receptor stimulation of calcium influx across the plasma membrane in phagocytes correlates strongly with the conversion of Ins(1,3,4,5)P3 to Ins(1,3,4,5)P4 by a Ca2(+)-calmodulin-sensitive kinase. The transduction system of phagocytosis receptors also generates DG and Ins(1,4,5)P3 and elicits [Ca2+]i elevations. The Ca2+ signal is an important regulator of secretion (granule exocytosis, superoxide production), whereas C kinase(s)/and other unknown mediators appear to be more important for the control of movement. Several mechanisms that could account for the specificity of cell signaling by different receptors are discussed.