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J Biol Chem, Vol. 274, Issue 40, 28134-28141, October 1, 1999

Inositol 1,4,5-Trisphosphate-independent Ca²⁺ Mobilization Triggered by a Lipid Factor Isolated from Vitreous Body

Jesus P. Camiña, Xesus Casabiell^§, and Felipe F. Casanueva

From the Departments of  Medicine and ^§ Physiology, Cellular Endocrinology Laboratory, Compostela University School of Medicine and Complejo Hospitalario Universitario de Santiago, E-15780 Santiago de Compostela, Spain

A complex phospholipid from bovine vitreous body with a strong Ca²⁺-mobilizing activity has been recently isolated to homogeneity by our group. In this work, a sequential analysis of its transmembrane signaling pathway has been undertaken to characterize the intracellular mechanisms responsible for the Ca²⁺ rise. The results show that this phospholipid induces, in a dose-dependent manner (ED₅₀ of around 0.25 µg/ml), a Ca²⁺ mobilization from inositol 1,4,5-trisphosphate-insensitive intracellular stores, with no participation of extracellular Ca²⁺. Upon repeated administration, it shows no signs of autologous desensitization, does not induce heterologous desensitization of the L--lysophosphatidic acid (LPA) receptor but is desensitized by the previous administration of LPA. The Ca²⁺-mobilizing activity requires a membrane protein, is blocked after preincubation of the cells with pertussis toxin and phorbol esters, as well as by U73122 (an inhibitor of phospholipases C/D), R59022 (a diacylglycerol kinase inhibitor), and D609 (which inhibits phosphatidylcholine-specific phospholipase C). Upon administration of this phospholipid, the intracellular levels of phosphatidic acid (PA) rise with a time course that parallels that of the Ca²⁺ mobilization, suggesting that PA could be responsible for this Ca²⁺ signal. Exposure to AACOCF₃ (a specific inhibitor of phospholipase A₂) does not modify the Ca²⁺ rise, ruling out the possibility that the PA generated could be further converted to LPA by the action of phospholipase A₂. Based on the experimental data obtained, a signaling pathway involving a phosphatidylcholine-specific phospholipase C coupled to diacylglycerol kinase is proposed. This compound may represent a new class of bioactive lipids with a putative role in the physiology of the vitreous body.

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