Differential regulation of human neutrophil FcγRIIa (CD32) and FcγRIIIb (CD16)-induced Ca2+ transients

Human neutrophils express two structurally distinct receptors for the Fc region of IgG, Fc gamma IIa and Fc gamma RIIIb, Although earlier studies have suggested that the functional properties of these receptors are similar, mounting evidence suggests that these receptors are capable of inducing distinct functional responses, Accordingly, we have examined the regulation of intracellular Ca2+ transients induced by each of these receptors alone (homotypic receptor cross-linking) and together (heterotypic receptor cross-linking), The glycosylphosphatidylinositol-anchored Fc gamma RIIIb induces a rise in [Ca2+] after homotypic cross-linking that is independent of ligand-mediated engagement of the transmembrane Fc gamma RIIa, Both receptors were sensitive to the protein-tyrosine kinase inhibitor methyl 2,5-dihydroxycinnamate, but Fc gamma RIIa-induced signaling was uniquely sensitive to the protein-tyrosine kinase inhibitor genistein, Fc gamma RIIa but not Fc gamma RIIIb engages a cAMP-sensitive and inositol 1,4,5-trisphosphate-dependent pathway(s) that results in the Ca2+-transient, When these receptors are cross-linked into heterotypic clusters, a synergistic rise in [Ca2+] is observed that is accompanied by synergistic increases in the phospholipase C gamma-breakdown products inositol 1,4,5-trisphosphate and diglyceride. These data provide a mechanism for the functional differences between these two receptors and suggest the possibility that they can be differentially modulated.