RGD Reference Report - Silencing of ZnT-1 expression enhances heavy metal influx and toxicity. - Rat Genome Database

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Silencing of ZnT-1 expression enhances heavy metal influx and toxicity.

Authors: Ohana, E  Sekler, I  Kaisman, T  Kahn, N  Cove, J  Silverman, WF  Amsterdam, A  Hershfinkel, M 
Citation: Ohana E, etal., J Mol Med (Berl). 2006 Sep;84(9):753-63. Epub 2006 Jun 2.
RGD ID: 8554228
Pubmed: (View Article at PubMed) PMID:16741752
DOI: Full-text: DOI:10.1007/s00109-006-0062-4

ZnT-1 reduces intracellular zinc accumulation and confers resistance against cadmium toxicity by a mechanism which is still unresolved. A functional link between the L-type calcium channels (LTCC) and ZnT-1 has been suggested, indicating that ZnT-1 may regulate ion permeation through this pathway. In the present study, immunohistochemical analysis revealed a striking overlap of the expression pattern of LTCC and ZnT-1 in cardiac tissue and brain. Using siRNA to silence ZnT-1 expression, we then assessed the role of ZnT-1 in regulating cation permeation through the L-type Ca(2+) channels in cells that are vulnerable to heavy metal permeation. Transfection of cortical neurons with ZnT-1 siRNA resulted in about 70% reduction of ZnT-1 expression and increased Ca(2+) influx via LTCC by approximately fourfold. Moreover, ZnT-1 siRNA transfected neurons showed approximately 30% increase in synaptic release, monitored using the FM1-43 dye. An increased cation influx rate, through the LTCC, was also recorded for Zn(2+) and Cd(2+) in cells treated with the ZnT-1 siRNA. Furthermore, Cd(2+)-induced neuronal death increased by approximately twofold after transfection with ZnT-1 siRNA. In addition, ZnT-1 siRNA transfection of the ovarian granulosa cell line, POGRS1, resulted in a twofold increase in Cd(2+) influx rate via the LTCC. Finally, a robust nimodipine-sensitive Cd(2+) influx was observed using a low extracellular Cd(2+) concentration (5 muM) in neurons and testicular slice cultures, attesting to the relevance of the LTCC pathway to heavy metal toxicity. Taken together, our results indicate that endogenously-expressed ZnT-1, by modulating LTCC, has a dual role: regulating calcium influx, and attenuating Cd(2+) and Zn(2+) permeation and toxicity in neurons and other cell types.

Gene Ontology Annotations    

Biological Process

Cellular Component
T-tubule  (IDA)

Molecular Function

Objects Annotated

Genes (Rattus norvegicus)
Slc30a1  (solute carrier family 30 member 1)

Additional Information