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J. Biol. Chem., Vol. 276, Issue 6, 4046-4054, February 9, 2001

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Inhibition of Sodium-Calcium Exchange by Ceramide and Sphingosine^*

Madalina Condrescu and John P. Reeves

From the Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, The New Jersey Medical School, Newark, New Jersey 07103

Na⁺/Ca²⁺ exchange activity in Chinese hamster ovary cells expressing the bovine cardiac Na⁺/Ca²⁺ exchanger was inhibited by the short chain ceramide analogs N-acetylsphingosine and N-hexanoylsphingosine (5-15 µM). The sphingolipids reduced exchange-mediated Ba²⁺ influx by 50-70% and also inhibited the Ca²⁺ efflux mode of exchange activity. The biologically inactive ceramide analog N-acetylsphinganine had only modest effects on exchange activity. Cells expressing the (241-680) and (680-685) deletion mutants of the Na⁺/Ca²⁺ exchanger were not inhibited by ceramide; these mutants show defects in both Na⁺-dependent and Ca²⁺-dependent regulatory behavior. Another mutant, which was defective only in Na⁺-dependent regulation, was as sensitive to ceramide inhibition as the wild-type exchanger. Inhibition of exchange activity by ceramide was time-dependent and was accelerated by depletion of internal Ca²⁺ stores. Sphingosine (2.5 µM) also inhibited the Ca²⁺ influx and efflux modes of exchange activity in cells expressing the wild-type exchanger; sphingosine did not affect Ba²⁺ influx in the (241-680) mutant. The effects of the exogenous sphingolipids were reproduced by blocking cellular ceramide utilization pathways, suggesting that exchange activity is inhibited by increased levels of endogenous ceramide and/or sphingosine. We propose that sphingolipids impair Ca²⁺-dependent activation of the exchanger and that in cardiac myocytes, this process serves as a feedback mechanism that links exchange activity to the diastolic concentration of cytosolic Ca²⁺.

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				S. J. Liu and R. H. Kennedy Positive inotropic effect of ceramide in adult ventricular myocytes: mechanisms dissociated from its reduction in Ca2+ influx Am J Physiol Heart Circ Physiol, July 11, 2003; 285(2): H735 - H744. [Abstract] [Full Text] [PDF]