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Originally published In Press as doi:10.1074/jbc.M110947200 on April 30, 2002

J. Biol. Chem., Vol. 277, Issue 27, 24265-24273, July 5, 2002
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Control of Calcium Homeostasis by Angiotensin II in Adrenal Glomerulosa Cells through Activation of p38 MAPK*

Irina StartchikDagger , Dominique MorabitoDagger , Ursula LangDagger , and Michel F. RossierDagger §

From the Dagger  Division of Endocrinology and Diabetology, Department of Internal Medicine, and the § Laboratory of Clinical Chemistry, Department of Pathology, University Hospital, CH-1211 Geneva 14, Switzerland

Angiotensin II-induced activation of aldosterone secretion in adrenal glomerulosa cells is mediated by an increase of intracellular calcium. We describe here a new Ca2+-regulatory pathway involving the inhibition by angiotensin II of calcium extrusion through the Na+/Ca2+ exchanger. Caffeine reduced both the angiotensin II-induced calcium signal and aldosterone production in bovine glomerulosa cells. These effects were independent of cAMP or calcium release from intracellular stores. The calcium response to angiotensin II was more sensitive to caffeine than the response to potassium, suggesting that the drug interacts with a pathway specifically elicited by the hormone. In calcium-free medium, calcium returned more rapidly to basal levels after angiotensin II stimulation in the presence of caffeine. Thapsigargin had no effect on these kinetics, but diltiazem, which inhibits the Na+/Ca2+ exchanger, markedly reduced the rate of calcium decrease and abolished caffeine action. The involvement of this exchanger was supported by the effect of cell depolarization and of a reduction of extracellular sodium on the rate of calcium extrusion. We also determined the mechanism of angiotensin II action on the exchanger. Phorbol esters reduced the rate of calcium extrusion, which was increased by baicalein, an inhibitor of lipoxygenases, and by SB 203580, an inhibitor of the p38 MAPK. Finally, we showed that angiotensin II acutely activates, in a caffeine-sensitive manner, p38 MAPK in glomerulosa cells. In conclusion, in bovine glomerulosa cells, the Na+/Ca2+ exchanger plays a crucial role in extruding calcium, and, by reducing its activity, angiotensin II influences the amplitude of the calcium signal. The hormone exerts its action on the exchanger through a caffeine-sensitive pathway involving the p38 MAPK and lipoxygenase products.

* This work was supported by Swiss National Science Foundation Grant 32-58948.99 and by a grant from the Jubiläumsstiftung der Schweizerischen Lebensversicherungs-und Rentenanstalt für Volksgesundheit und medizinische Forschung.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Division of Endocrinology and Diabetology, University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. Tel.: 41-22-3729320; Fax: 41-22-3729329; E-mail: rossier@cmu.unige.ch.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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