Relationship of phosphatidylinositol bisphosphate hydrolysis to calcium mobilization and functional activation in fluoride-treated neutrophils

Sodium fluoride (20 mM) effected rapid hydrolysis of phosphatidylinositol bisphosphate (PIP₂) in human neutrophils. Intracellular free Ca²⁺ levels increased after PIP₂ hydrolysis but before respiratory burst activation. Both the increase in intracellular free Ca²⁺ levels and the extent of functional activation were dependent on the availability of extracellular Ca²⁺. The rate of F^--stimulated PIP₂ hydrolysis, however, was not affected when the rise in cytosolic Ca²⁺ was severely limited by depletion of extracellular Ca²⁺. Fluoride caused the specific hydrolysis of PIP₂ in isolated neutrophil plasma membranes. This effect occurred in the presence of low levels of available Ca²⁺ and was accompanied by the release of inositol phosphates. We conclude that PIP₂ hydrolysis is an early event in the response of neutrophils to F^-. This response is not Ca²⁺-regulated but many lead to an influx of Ca²⁺ from the extracellular medium. Activation of a PIP₂-specific phsopholipase independent of a change in cytosolic free Ca²⁺ levels may be the initial event in the stimulus-response pathway triggered by fluoride.