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J. Biol. Chem., Vol. 276, Issue 16, 13198-13208, April 20, 2001

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Studies of Insulin Secretory Responses and of Arachidonic Acid Incorporation into Phospholipids of Stably Transfected Insulinoma Cells That Overexpress Group VIA Phospholipase A₂ (iPLA₂) Indicate a Signaling Rather Than a Housekeeping Role for iPLA₂^*

Zhongmin Ma, Sasanka Ramanadham, Mary Wohltmann, Alan Bohrer, Fong-Fu Hsu, and John Turk

From the Mass Spectrometry Resource, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110

A cytosolic 84-kDa group VIA phospholipase A₂ (iPLA₂) that does not require Ca²⁺ for catalysis has been cloned from several sources, including rat and human pancreatic islet -cells and murine P388D1 cells. Many potential iPLA₂ functions have been proposed, including a signaling role in -cell insulin secretion and a role in generating lysophosphatidylcholine acceptors for arachidonic acid incorporation into P388D1 cell phosphatidylcholine (PC). Proposals for iPLA₂ function rest in part on effects of inhibiting iPLA₂ activity with a bromoenol lactone (BEL) suicide substrate, but BEL also inhibits phosphatidate phosphohydrolase-1 and a group VIB phospholipase A₂. Manipulation of iPLA₂ expression by molecular biologic means is an alternative approach to study iPLA₂ functions, and we have used a retroviral construct containing iPLA₂ cDNA to prepare two INS-1 insulinoma cell clonal lines that stably overexpress iPLA₂. Compared with parental INS-1 cells or cells transfected with empty vector, both iPLA₂-overexpressing lines exhibit amplified insulin secretory responses to glucose and cAMP-elevating agents, and BEL substantially attenuates stimulated secretion. Electrospray ionization mass spectrometric analyses of arachidonic acid incorporation into INS-1 cell PC indicate that neither overexpression nor inhibition of iPLA₂ affects the rate or extent of this process in INS-1 cells. Immunocytofluorescence studies with antibodies directed against iPLA₂ indicate that cAMP-elevating agents increase perinuclear fluorescence in INS-1 cells, suggesting that iPLA₂ associates with nuclei. These studies are more consistent with a signaling than with a housekeeping role for iPLA₂ in insulin-secreting -cells.

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