L-type Ca2+ channel-mediated Zn2+ toxicity and modulation by ZnT-1 in PC12 cells

Albert H. Kim, Christian T. Sheline, Min Tian, Toshio Higashi, Robert J. McMahon, Robert J. Cousins, Dennis W. Choi

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92 Scopus citations


In view of evidence that Zn2+ neurotoxicity contributes to some forms of pathological neuronal death, we developed a model of Zn2+ neurotoxicity in a cell line amenable to genetic manipulations. Exposure to 500 μM ZnCl2 for 15 min under depolarizing conditions resulted in modest levels of PC12 cell death, that was reduced by the L-type Ca2+ channel antagonist, nimodipine, and increased by the L-type Ca2+ channel opener, S(-)-Bay K 8644. At lower insult levels (200 μM Zn2++Bay K 8644), Zn2+-induced death appeared apoptotic under electron microscopy and was sensitive to the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-CH2F (Z-VAD); at higher insult levels (1000 μM+Bay K 8644), cells underwent necrosis insensitive to Z-VAD. To test the hypothesis that the plasma membrane transporter, ZnT-1, modulates Zn2+ neurotoxicity, we generated stable PC12 cell lines overexpressing wild type or dominant negative forms of rat ZnT-1 (rZnT-1). Clones T9 and T23 overexpressing wild type rZnT-1 exhibited enhanced Zn2+ efflux and reduced vulnerability to Zn2+-induced death compared to the parental line, whereas clones D5 and D16 expressing dominant negative rZnT-1 exhibited the opposite characteristics. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish
Pages (from-to)99-107
Number of pages9
JournalBrain Research
Issue number1-2
StatePublished - Dec 15 2000


  • Bay K 8644
  • Cell death
  • PC12
  • Zinc
  • ZnT-1


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