Cellular regulation of sodium-calcium exchange.
Na(+)/Ca(2+) exchange activity was studied in transfected Chinese hamster ovary (CHO) cells expressing the wild-type cardiac exchanger (NCX1.1) or mutants created by site-directed mutagenesis. The activity of the wild-type exchanger, but not exchanger mutants deficient in Ca(2+)-dependent activation, was inhibited by sphingolipids such as ceramide and sphingosine. We propose that sphingolipids interfere with the regulatory activation of exchange activity by Ca(2+) and suggest that this interaction provides a means for monitoring and regulating diastolic Ca(2+) levels in beating cardiac myocytes. Exchange activity in CHO cells was also linked, through a poorly understood feedback mechanism, to Ca(2+) accumulation within internal stores such as the endoplasmic reticulum and the mitochondria. Finally, the F-actin cytoskeleton was shown to modulate exchange activity through interactions involving the exchanger's central hydrophilic domain. We conclude that regulation of exchange activity in intact cells involves multiple interactions with various lipid species, cytosolic Ca(2+), organellar Ca(2+) stores, and the cytoskeleton.
Condrescu
Madalina
M
Department of Pharmacology and Physiology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School and Graduate School of Biomedical Sciences, Newark, New Jersey 07103, USA.
Opuni
Kwabena
K
Hantash
Basil M
BM
Reeves
John P
JP
D000818:Animals; D001369:Axons / Q000502:physiology*; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology; D006224:Cricetinae; D003600:Cytosol / Q000502:physiology; D049832:Decapodiformes; D047630:Depsipeptides; D006321:Heart / Q000502:physiology*; D008387:Marine Toxins; D008928:Mitochondria / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009200:Myocardial Contraction / Q000502:physiology*; D010080:Oxazoles / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000187:drug effects / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014162:Transfection
D015220:Calcium Channels; D047630:Depsipeptides; D008387:Marine Toxins; C064769:N-acetylsphingosine; D010080:Oxazoles; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; C057531:jasplakinolide; C059041:calyculin A; D012964:Sodium; D013110:Sphingosine; D002118:Calcium