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Mitochondrial Ca2+ uptake from plasma membrane Cav3.2 protein channels contributes to ischemic toxicity in PC12 cells.

Abstract
T-type Ca(2+) channel inhibitors protect hippocampal CA1 neurons from delayed death after global ischemia in rats, suggesting that Cav3.1, Cav3.2, or Cav3.3 channels generate cytotoxic Ca(2+) elevations during anoxia. To test this hypothesis, we measured the Ca(2+) concentration changes evoked by oxygen and glucose deprivation (OGD) in the cytosol and in the mitochondria of PC12 cells. OGD evoked long-lasting cytosolic Ca(2+) elevations that were reduced by Cav3.2 inhibition (50 μm Ni(2+)) and Cav3.1/Cav3.2 silencing and potentiated by Cav3.2 overexpression. The kinetics of the sustained cytosolic Ca(2+) elevations occurring during OGD directly correlated to the extent of cell death measured 20 h after reoxygenation, which was decreased by Ni(2+) and Cav3.1/Cav3.2 silencing and increased by Cav3.2 overexpression. Ni(2+) and Cav3.1/Cav3.2 silencing delayed the decline of cellular ATP during OGD, consistent with a reduction in the Ca(2+) load actively extruded by plasma membrane Ca(2+) pumps. The cytosolic Ca(2+) elevations were paralleled by mitochondrial Ca(2+) elevations that were also increased by Cav3.2 overexpression and decreased by Ni(2+) but not by Cav3.1/Cav3.2 silencing. Overexpression and silencing of the mitochondrial Ca(2+) uniporter, the major mitochondrial Ca(2+) uptake protein, revealed that the cytotoxicity was correlated to the amplitude of the mitochondrial, rather than the cytosolic, Ca(2+) elevations. Selective activation of T-type Ca(2+) channels evoked both cytosolic and mitochondrial Ca(2+) elevations, but only the mitochondrial responses were reduced by Cav3.1/Cav3.2 silencing. We conclude that the opening of Cav3.2 channels during ischemia contribute to the entry of Ca(2+) ions that are transmitted to mitochondria, resulting in a deleterious mitochondrial Ca(2+) overload.
AuthorsYves Gouriou, Philippe Bijlenga, Nicolas Demaurex
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 18 Pg. 12459-68 (May 03 2013) ISSN: 1083-351X [Electronic] United States
PMID23508951 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Cacna1g protein, rat
  • Cacna1h protein, rat
  • Calcium Channels, T-Type
  • Adenosine Triphosphate
  • Calcium
Topics
  • Adenosine Triphosphate (genetics, metabolism)
  • Animals
  • Calcium (metabolism)
  • Calcium Channels, T-Type (genetics, metabolism)
  • Cell Hypoxia
  • Cell Membrane (genetics, metabolism)
  • Cytoplasm (genetics, metabolism)
  • Gene Silencing
  • Mitochondria (genetics, metabolism)
  • PC12 Cells
  • Rats

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