Platelet-activating factor may stimulate both receptor-dependent and receptor-independent increases in [Ca2+] in...

Platelet-activating factor (PAF) is a potent mediator which produces a wide range of biological responses by binding to specific, high affinity receptors on the target cell surface. In addition, we and others have observed cellular responses to PAF which are not receptor-mediated. We report here that in HBE-16 human bronchial epithelial cells, PAF produces a biphasic increase in [Ca2+]i consisting of a rapid initial increase due to release from intracellular stores followed by a gradual, sustained phase caused by influx of extracellular Ca2+. Under certain conditions, the PAF receptor antagonist L-659,989 completely blocks the release of Ca2+ from intracellular stores, suggesting a complete block of the receptor-mediated response. Under these same conditions, a residual influx of extracellular Ca2+ is observed, suggesting a possible receptor-independent response. HBE-16 cells partially metabolize PAF to 1-O-alkyl-2-acetyl-sn-glycerol (AAG), a bioactive diacylglycerol analog. Moreover, AAG stimulates Ca2+ influx in these cells; the response to AAG is at least 100-fold more potent than that to PAF. Taken together, these results suggest that PAF may stimulate Ca2+ influx in HBE-16 cells through a receptor-independent pathway mediated by AAG. Thus these studies suggest a previously unrecognized dual-pathway regulatory mechanism for PAF in the airway.