POLYENOIC VERY-LONG-CHAIN FATTY-ACIDS MOBILIZE INTRACELLULAR CALCIUM FROM A THAPSIGARGIN-INSENSITIVE POOL IN HUMAN NEUTROPHILS - THE RELATIONSHIP BETWEEN CA2-CHAIN AND VERY-LONG-CHAIN FATTY-ACIDS( MOBILIZATIONAND SUPEROXIDE PRODUCTION INDUCED BY LONG)

Fatty acids with more than 22 carbon atoms (very-long-chain fatty acid s; VLCFAs) are normal cellular components that have been implicated in the pathophysiology of a number of peroxisomal disorders. To date, ho wever, essentially nothing is known regarding their biological activit ies. Ca2+ mobilization is an important intracellular signalling system for a variety of agonists and cell types. Given that several polyunsa turated long-chain fatty acids mobilize intracellular Ca2+ and that we have postulated that the VLCFAs may be involved in signal transductio n, we examined whether the tetraenoic VLCFA induced Ca2+ mobilization in; human neutrophils. We report that fatty acid-induced intracellular Ca2+ mobilization declined for fatty acid species of more than 20 car bon atoms, but increased again as the carbon chain length approached 3 0. This Ca2+ mobilization occurred independently of inositol 1,4,5-tri sphosphate production and protein kinase C translocation and involved both the release of Ca2+ from the intracellular stores and changes to the influx or efflux of the ion. We further observed that triacontatet raenoic acid [30:4 (n-6)] mobilized Ca2+ from a thapsigargin-insensiti ve intracellular pool distinct from the thapsigargin-sensitive pools a ffected by arachidonic acid [20:4 (n-6)] or N-formyl-L-methionyl-L-leu cyl-L-phenylalanine (fMLP). 20:4 (n-6) induced strong superoxide produ ction (chemiluminescence) which was inhibited by thapsigargin pretreat ment. In contrast, fatty acid-induced superoxide production progressiv ely declined as the carbon chain length increased beyond 20-22 carbon atoms. Further studies suggested that the thapsigargin-insensitive Ca2 + mobilization elicited by 30:4 (n-6) was not related to oxy radical f ormation, while the-thapsigargin-sensitive Ca2+ mobilization induced b y 20:4 (n-6) may be involved in the initiation but not necessarily the maintenance of superoxide production. In conclusion, this is the firs t report to demonstrate a biological activity for the VLCFA and indica tes that 30:4 (n-6) influences second messenger systems in intact cell s that differ from those affected by long-chain fatty acids such as 20 :4 (n-6).