Volume 271, Number 46, Issue of November 15, 1996 pp. 29205-29210
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Hydroperoxide-induced Increases in Intracellular Calcium Due to Annexin VI Translocation and Inactivation of Plasma Membrane Ca²⁺-ATPase

(Received for publication, May 30, 1996, and in revised form, August 20, 1996)

Carolyn R. Hoyal , Andrew P. Thomas ^§ and Henry Jay Forman

From the  Departments of Molecular Pharmacology and Toxicology and Pathology, University of Southern California, Los Angeles, California 90033 and the ^§ Department of Anatomy, Pathology, and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Oxidative stress can cause changes in intracellular free calcium concentration ([Ca²⁺]_i) that resemble those occurring under normal cell signaling. In the alveolar macrophage, hydroperoxide-induced elevation of [Ca²⁺]_i modulates the respiratory burst and other important physiologic functions. The source of Ca²⁺ released by hydroperoxide is intracellular but separate from the endoplasmic reticulum pool released by receptor-mediated stimuli (Hoyal, C. R., Gozal, E., Zhou, H., Foldenauer, K., and Forman, H. J. (1996) Arch. Biochem. Biophys. 326, 166-171). Previous studies in other cells have suggested that mitochondria are a potential source of oxidant-induced [Ca²⁺]_i elevation. In this study we have identified another potential source of hydroperoxide-releasable intracellular calcium, that bound to annexin VI on the inner surface of the plasma membrane. Translocation of annexin VI from the membrane during exposure to t-butyl hydroperoxide matched elevation of [Ca²⁺]_i as a function of time and t-butyl hydroperoxide concentration. The translocation was possibly due to a combination of ATP depletion and oxidative modification of membrane lipids and proteins. A sustained increase in [Ca²⁺]_i occurring > 50 pmol/10⁶ cells (50 µM under these conditions) appeared to be a consequence of membrane Ca²⁺-ATPase dysfunction. These results suggest that exposure to oxidative stress results in early alterations to the plasma membrane and concomitant release of Ca²⁺ into the cytosol. In addition it suggests a mechanism for participation of annexin VI translocation that may underlie the alterations in macrophage function by oxidative stress.

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