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J Biol Chem, Vol. 274, Issue 41, 29529-29535, October 8, 1999

Na⁺/Ca²⁺ Exchange Facilitates Ca²⁺-dependent Activation of Endothelial Nitric-oxide Synthase

Margot Teubl, Klaus Groschner, Sepp D. Kohlwein, Bernd Mayer, and Kurt Schmidt

From the Institut für Pharmakologie und Toxikologie, Karl-Franzens-Universität Graz, Universitätsplatz 2 and the  Institut für Biochemie und Lebensmittelchemie, Technische Universität Graz, Petersgasse 12, A-8010 Graz, Austria

Recent evidence suggests the expression of a Na⁺/Ca²⁺ exchanger (NCX) in vascular endothelial cells. To elucidate the functional role of endothelial NCX, we studied Ca²⁺ signaling and Ca²⁺-dependent activation of endothelial nitric-oxide synthase (eNOS) at normal, physiological Na⁺ gradients and after loading of endothelial cells with Na⁺ ions using the ionophore monensin. Monensin-induced Na⁺ loading markedly reduced Ca²⁺ entry and, thus, steady-state levels of intracellular free Ca²⁺ ([Ca²⁺]_i) in thapsigargin-stimulated endothelial cells due to membrane depolarization. Despite this reduction of overall [Ca²⁺]_i, Ca²⁺-dependent activation of eNOS was facilitated as indicated by a pronounced leftward shift of the Ca²⁺ concentration response curve in monensin-treated cells. This facilitation of Ca²⁺-dependent activation of eNOS was strictly dependent on the presence of Na⁺ ions during treatment of the cells with monensin. Na⁺-induced facilitation of eNOS activation was not due to a direct effect of Na⁺ ions on the Ca²⁺ sensitivity of the enzyme. Moreover, the effect of Na⁺ was not related to Na⁺ entry-induced membrane depolarization or suppression of Ca²⁺ entry, since neither elevation of extracellular K⁺ nor the Ca²⁺ entry blocker 1-(-[3-(4-methoxyphenyl)-propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride (SK&F 96365) mimicked the effects of Na⁺ loading. The effects of monensin were completely blocked by 3',4'-dichlorobenzamil, a potent and selective inhibitor of NCX, whereas the structural analog amiloride, which barely affects Na⁺/Ca²⁺ exchange, was ineffective. Consistent with a pivotal role of Na⁺/Ca²⁺ exchange in Ca²⁺-dependent activation of eNOS, an NCX protein was detected in caveolin-rich membrane fractions containing both eNOS and caveolin-1. These results demonstrate for the first time a crucial role of cellular Na⁺ gradients in regulation of eNOS activity and suggest that a tight functional interaction between endothelial NCX and eNOS may take place in caveolae.

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