Journal
CELL CALCIUM
Volume 59, Issue 5, Pages 251-261Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ceca.2016.02.014
Keywords
Prolonged ischemic conditions; Intracellular free Ca2+ concentration; ([Ca2+](i)); HIF-1 alpha; Ca2+-ATPase; SERCA2b; CA1 and CA3 hippocampal neurons
Categories
Funding
- NASU Biotechnology
- Functional Genomics
- DFFD [F47/066]
- NASU Nanotechnology
- Functional Genomics and Metabolomics grants
- NASU
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Pyramidal neurons of the hippocampus possess differential susceptibility to the ischemia-induced damage with the highest vulnerability of CA1 and the lower sensitivity of CA3 neurons. This damage is triggered by Ca2+-dependent excitotoxicity and can result in a delayed cell death that might be potentially suspended through activation of endogenous neuroprotection with the hypoxia-inducible transcription factors (HIF). However, the molecular mechanisms of this neuroprotection remain poorly understood. Here we show that prolonged (30 min) oxygen and glucose deprivation (OGD) in situ impairs intracellular Ca2+ regulation in CA1 rather than in CA3 neurons with the differently altered expression of genes coding Ca2+-ATPases: the mRNA level of plasmalemmal Ca2+-ATPases (PMCA1 and PMCA2 subtypes) was downregulated in CA1 neurons, whereas the mRNA level of the endoplasmic reticulum Ca2+-ATPases (SERCA2b subtype) was increased in CA3 neurons at 4 h of re-oxygenation after prolonged OGD. These demonstrate distinct susceptibility of CAI and CA3 neurons to the ischemic impairments in intracellular Ca2+ regulation and Ca2+-ATPase expression. Stabilization of HIF-1 alpha by inhibiting HIF-1 alpha hydroxylation prevented the ischemic decrease in both PMCA1 and PMCA2 mRNAs in CA1 neurons, upregulated the SERCA2b mRNA level and eliminated the OGD-induced Ca2+ store dysfunction in these neurons. Cumulatively, these findings reveal the previously unknown HIF-la-driven upregulation of Ca2+-ATPases as a mechanism opposing the ischemic impairments in intracellular Ca2+ regulation in hippocampal neurons. The ability of HIF-1 alpha to modulate expression of genes coding Ca2+-ATPases suggests SERCA2b as a novel target for HIF-1 and may provide potential implications for HIF-1 alpha-stabilizing strategy in activating endogenous neuroprotection. (C) 2016 Elsevier Ltd. All rights reserved.
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