title: 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.
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.
authors.affiliation: Laboratory of Sensory Signaling, Bogomoletz Institute of Physiology, Kyiv, Ukraine.
authors.forename: Olga
authors.initials: O
authors.lastname: Kopach
authors.affiliation: Department of Cytology, Bogomoletz Institute of Physiology, Kyiv, Ukraine.
authors.forename: Anastasiia
authors.initials: A
authors.lastname: Maistrenko
authors.affiliation: Department of Cytology, Bogomoletz Institute of Physiology, Kyiv, Ukraine.
authors.forename: Iryna
authors.initials: I
authors.lastname: Lushnikova
authors.affiliation: Laboratory of Molecular Biophysics, Bogomoletz Institute of Physiology, Kyiv, Ukraine; International Center for Molecular Physiology, Bogomoletz Institute of Physiology, Kyiv, Ukraine.
authors.forename: Pavel
authors.initials: P
authors.lastname: Belan
authors.affiliation: Department of Cytology, Bogomoletz Institute of Physiology, Kyiv, Ukraine.
authors.forename: Galina
authors.initials: G
authors.lastname: Skibo
authors.affiliation: Laboratory of Sensory Signaling, Bogomoletz Institute of Physiology, Kyiv, Ukraine; International Center for Molecular Physiology, Bogomoletz Institute of Physiology, Kyiv, Ukraine. Electronic address: nana@biph.kiev.ua.
authors.forename: Nana
authors.initials: N
authors.lastname: Voitenko
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D017208:Rats, Wistar; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C506948:Atp2a2 protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018696:Neuroprotective Agents; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium
keywords: CA1 and CA3 hippocampal neurons; Ca(2+)-ATPase; HIF-1α; Intracellular free Ca(2+) concentration ([Ca(2+)](i)); Prolonged ischemic conditions; SERCA2b