HIF-1α-mediated upregulation of SERCA2b: The endogenous mechanism for alleviating the ischemia-induced intracellular Ca(2+) store dysfunction in CA1 and CA3 hippocampal neurons

Cell Calcium. 2016 May;59(5):251-61. doi: 10.1016/j.ceca.2016.02.014. Epub 2016 Mar 3.

Abstract

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 Ca(2+)-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 (30min) oxygen and glucose deprivation (OGD) in situ impairs intracellular Ca(2+) regulation in CA1 rather than in CA3 neurons with the differently altered expression of genes coding Ca(2+)-ATPases: the mRNA level of plasmalemmal Ca(2+)-ATPases (PMCA1 and PMCA2 subtypes) was downregulated in CA1 neurons, whereas the mRNA level of the endoplasmic reticulum Ca(2+)-ATPases (SERCA2b subtype) was increased in CA3 neurons at 4h of re-oxygenation after prolonged OGD. These demonstrate distinct susceptibility of CA1 and CA3 neurons to the ischemic impairments in intracellular Ca(2+) regulation and Ca(2+)-ATPase expression. Stabilization of HIF-1α by inhibiting HIF-1α hydroxylation prevented the ischemic decrease in both PMCA1 and PMCA2 mRNAs in CA1 neurons, upregulated the SERCA2b mRNA level and eliminated the OGD-induced Ca(2+) store dysfunction in these neurons. Cumulatively, these findings reveal the previously unknown HIF-1α-driven upregulation of Ca(2+)-ATPases as a mechanism opposing the ischemic impairments in intracellular Ca(2+) regulation in hippocampal neurons. The ability of HIF-1α to modulate expression of genes coding Ca(2+)-ATPases suggests SERCA2b as a novel target for HIF-1 and may provide potential implications for HIF-1α-stabilizing strategy in activating endogenous neuroprotection.

Keywords: CA1 and CA3 hippocampal neurons; Ca(2+)-ATPase; HIF-1α; Intracellular free Ca(2+) concentration ([Ca(2+)](i)); Prolonged ischemic conditions; SERCA2b.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Cell Death / drug effects
  • Cytoplasm / metabolism
  • Down-Regulation / drug effects
  • Hippocampus / metabolism*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Ischemia / metabolism
  • Neurons / metabolism*
  • Neuroprotective Agents / pharmacology
  • Rats, Wistar
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • Transcriptional Activation / drug effects
  • Up-Regulation / drug effects

Substances

  • Atp2a2 protein, rat
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Neuroprotective Agents
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium