Cyclosporin A-Dependent Downregulation of the Na+/Ca2+ Exchanger Expression

Autor:	Hannah Rahamimoff, M. Eskin-Shwartz, Chava Kimchi-Sarfaty, Benayahu Elbaz, A. Alperovich, Michael M. Gottesman, Judith Kasir, Y. Lichtenstein
Rok vydání:	2007
Předmět:	Protein Folding Protein domain Down-Regulation chemistry.chemical_element Calcium Biology Sodium-Calcium Exchanger General Biochemistry Genetics and Molecular Biology Cell Line History and Philosophy of Science Downregulation and upregulation Cyclosporin a Animals Humans Cells Cultured Cyclophilin DNA Primers chemistry.chemical_classification Base Sequence Reverse Transcriptase Polymerase Chain Reaction General Neuroscience HEK 293 cells Transfection Molecular biology Rats Amino acid chemistry Cyclosporine cardiovascular system
Zdroj:	Annals of the New York Academy of Sciences. 1099:204-214
ISSN:	0077-8923
DOI:	10.1196/annals.1387.046
Popis:	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 + /Ca 2+ 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 + /Ca 2+ 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 + /Ca 2+ 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 from the 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.
Databáze:	OpenAIRE
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