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M110947200v1
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Papers In Press, published online ahead of print April 30, 2002
J. Biol. Chem, 10.1074/jbc.M110947200
Submitted on November 15, 2001
Revised on April 30, 2002
Accepted on April 30, 2002

Control of calcium homeostasis by angiotensin II in adrenal glomerulosa cells through activation of p38 mitogen-activated protein kinase (MAPK)

Irina Startchik, Dominique Morabito, Ursula Lang, and Michel F. Rossier

Division of Endocrinology & Diabetology, University Hospital of Geneva, Geneva 14 CH-1211

Corresponding Author: Michel.Rossier{at}medecine.unige.ch

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, that 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 SB203580, an inhibitor of the p38 mitogen-activated protein kinase (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.


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