Interactive report 2 1 2 1 L - type Ca channel - mediated Zn toxicity and modulation 1 by ZnT - 1 in PC 12 cells

21 21 In view of evidence that Zn neurotoxicity contributes to some forms of pathological neuronal death, we developed a model of Zn neurotoxicity in a cell line amenable to genetic manipulations. Exposure to 500 mM ZnCl for 15 min under depolarizing conditions 2 21 resulted in modest levels of PC12 cell death, that was reduced by the L-type Ca channel antagonist, nimodipine, and increased by the 21 21 21 L-type Ca channel opener, S(2)-Bay K 8644. At lower insult levels (200 mM Zn 1Bay K 8644), Zn -induced death appeared apoptotic under electron microscopy and was sensitive to the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-CH F (Z-VAD); at higher 2 insult levels (1000 mM1Bay K 8644), cells underwent necrosis insensitive to Z-VAD. To test the hypothesis that the plasma membrane 21 transporter, ZnT-1, modulates Zn neurotoxicity, we generated stable PC12 cell lines overexpressing wild type or dominant negative 21 forms of rat ZnT-1 (rZnT-1). Clones T9 and T23 overexpressing wild type rZnT-1 exhibited enhanced Zn efflux and reduced 21 vulnerability to Zn -induced death compared to the parental line, whereas clones D5 and D16 expressing dominant negative rZnT-1 exhibited the opposite characteristics.  2000 Elsevier Science B.V. All rights reserved. Theme: Disorders of the nervous system Topic: Neurotoxicity