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Mass Spectrometric Evidence That Agents That Cause Loss of Ca²⁺ from Intracellular Compartments Induce Hydrolysis of Arachidonic Acid from Pancreatic Islet Membrane Phospholipids by a Mechanism That Does Not Require a Rise in Cytosolic Ca²⁺ Concentration¹

Mass Spectrometry Resource, Divisions of Diabetes, Endocrinology, and Metabolism and of Laboratory Medicine, Departments of Medicine and Pathology, Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence and requests for reprints to: John Turk, Washington University School of Medicine, Box 8127, 660 S. Euclid Avenue, St. Louis, Missouri 63110. E-mail: jturk{at}imgate.wustl.edu

Stimulation of pancreatic islets with glucose induces phospholipid hydrolysis and accumulation of nonesterified arachidonic acid, which may amplify the glucose-induced Ca²⁺ entry into islet ß-cells that triggers insulin secretion. Ca²⁺ loss from ß-cell intracellular compartments has been proposed to induce both Ca²⁺ entry and events dependent on arachidonate metabolism. We examine here effects of inducing Ca²⁺ loss from intracellular sequestration sites with ionophore A23187 and thapsigargin on arachidonate hydrolysis from islet phospholipids. A23187 induces a decline in islet arachidonate-containing phospholipids and release of nonesterified arachidonate. A23187-induced arachidonate release is of similar magnitude when islets are stimulated in Ca²⁺-replete or in Ca²⁺-free media or when islets loaded with the intracellular Ca²⁺ chelator BAPTA are stimulated in Ca²⁺-free medium, a condition in which A23187 induces no rise in ß-cell cytosolic [Ca²⁺]. Thapsigargin also induces islet arachidonate release under these conditions. A23187- or thapsigargin-induced arachidonate release is prevented by a bromoenol lactone (BEL) inhibitor of a ß-cell phospholipase A₂ (iPLA₂), which does not require Ca²⁺ for catalytic activity and which is negatively modulated by and physically interacts with calmodulin by Ca²⁺-dependent mechanisms. Agents that cause Ca²⁺ loss from islet intracellular compartments thus induce arachidonate hydrolysis from phospholipids by a BEL-sensitive mechanism that does not require a rise in cytosolic [Ca²⁺], and a BEL-sensitive enzyme-like iPLA₂ or a related membranous activity may participate in sensing Ca²⁺ compartment content.

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