Cyclosporin A-dependent downregulation of the Na+/Ca 2+ exchanger expression

Hannah Rahamimoff*, B. Elbaz, A. Alperovich, C. Kimchi-Sarfaty, M. M. Gottesman, Y. Lichtenstein, M. Eskin-Shwartz, J. Kasir

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingConference contribution

8 Scopus citations

Abstract

Cyclosporin A (CsA) is an immunosuppressive drug commonly given to transplant patients. Its application is accompanied by severe side effects related to calcium, among them hypertension and nephrotoxicity. The Na +/Ca2+ exchanger (NCX) is a major calcium regulator expressed in the surface membrane of all excitable and many nonexcitable tissues. Three genes, NCX1, NCX2, and NCX3 code for Na+/Ca 2+ exchange activity. NCX1 gene products are the most abundant. We have shown previously that exposure of NCX1-transfected HEK 293 cells to CsA, leads to concentration-dependent reduction of Na+/Ca2+ exchange activity and surface expression, without a reduction in total cell-expressed NCX1 protein. We show now that the effect of CsA on NCX1 protein expression is not restricted to transfected cells overexpressing the NCX1 protein but exhibited also in cells expressing endogenously the NCX1 protein (L6, H9c2, and primary smooth muscle cells). Exposure of NCX2- and NCX3-transfected cells to CsA results also in reduction of Na +/Ca2+ exchange activity and surface expression, though the sensitivity to the drug was lower than in NCX1-transfected cells. Studying the molecular mechanism of CsA-NCX interaction suggests that cyclophilin (Cyp) is involved in NCX1 protein expression and its modulation by CsA. Deletion of 426 amino acids fromthe large cytoplasmic loop of the protein retains the CsA-dependent downregulation of the truncated NCX1 suggesting that CsA-Cyp-NCX interaction involves the remaining protein domains.

Original languageEnglish (US)
Title of host publicationSodium-Calcium Exchange and the Plasma Membrane Ca2+ATPase in Ce;; Funcyion
Subtitle of host publicationFifth International Conference
PublisherBlackwell Publishing Inc.
Pages204-214
Number of pages11
ISBN (Print)1573316490, 9781573316491
DOIs
StatePublished - Mar 2007

Publication series

NameAnnals of the New York Academy of Sciences
Volume1099
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Cyclophilin A
  • Cyclosporin A
  • Na/Ca exchanger expression
  • Proline mutagenesis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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    Rahamimoff, H., Elbaz, B., Alperovich, A., Kimchi-Sarfaty, C., Gottesman, M. M., Lichtenstein, Y., Eskin-Shwartz, M., & Kasir, J. (2007). Cyclosporin A-dependent downregulation of the Na+/Ca 2+ exchanger expression. In Sodium-Calcium Exchange and the Plasma Membrane Ca2+ATPase in Ce;; Funcyion: Fifth International Conference (pp. 204-214). (Annals of the New York Academy of Sciences; Vol. 1099). Blackwell Publishing Inc.. https://doi.org/10.1196/annals.1387.046