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First published on January 8, 2008; DOI: 10.1124/mol.107.041582

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Received for publication September 6, 2007.
Revised January 6, 2008.
Accepted for publication January 7, 2008.

MODULATION OF NCX (Na+-Ca2+ EXCHANGER) EXPRESSION BY IMMUNOSUPPRESSIVE DRUGS IS ISOFORM SPECIFIC

Benayahu Elbaz 1, Ariella Alperovitch 2, Michael M Gottesman 3, Chava Kimchi-Sarfaty 4, Hannah Rahamimoff 2*

1 Department of Biochemistry, Hebrew University - Hadassah Medical School, Jerusalem, Israel 2 Department of Biochemistry Hebrew University - Hadassah Medical School, Jerusalem, Israel, 3 Laboratory of Cell Biology, NCI, NIH, Bethesda MD 4 Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD

* Address correspondence to: E-mail: hannah.rahamimoff{at}huji.ac.il

Abstract

The Na+-Ca2+ exchanger is a major Ca2+ regulating protein encoded by three genes: NCX1, NCX2 and NCX3.They share about 65% sequence homology. NCX1 protein is expressed ubiquitously and NCX2 and NCX3 are expressed almost exclusively in the brain. We have shown previously (Kimchi-Sarfaty et al., 2002), that treatment of NCX1-transfected HEK 293 cells with the immunosuppressive Cyclosporin A and its non-immunosuppressive analogue PSC833 results in down regulation of surface expression and transport activity of the protein without a decrease in expression of cell NCX1 protein. We show now that Cyclosporin A and PSC833 treatment of NCX2 and NCX3 transfected HEK 293 cells resulted also in dose-dependent down-regulation of surface expression and transport activity of the two brain NCX proteins; But whereas CsA had no effect on total cell NCX protein expression, PSC833 reduced mRNA and cell protein expression of NCX2 and NCX3. Moreover, tacrolimus (FK506) which had no effect on NCX1 protein expression, down-regulated NCX2 and NCX3 surface expression and transport activity without any significant effect on cell protein expression. Sirolimus (Rapamycin) had no effect on NCX2 and NCX3 protein expression yet it reduced NCX2 and NCX3 transport activity. Since all the experimental conditions in our studies were identical, presumably the different drug response is related to structural differences between NCX isoforms. Clinical studies suggested that immunosuppressive regimes of transplant patients resulted in complications related to Ca2+ . Expression of NCX genes is tissue specific. Hence, our results can potentially provide a tool for choice of the immunosuppressive protocol to be used.


Key words: Ion transporters (SERCA, Na/K ATPase, CFTR), Structure-activity relationships and modeling, Regulation - post-transcriptional, Structure/function/mechanism




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