title: SK channel activation modulates mitochondrial respiration and attenuates neuronal HT-22 cell damage induced by H2O2.
abstract: Previous studies established an essential role for small conductance calcium-activated potassium (SK) channels in neuronal cell death pathways induced by glutamate excitotoxicity in cortical neurons in vitro and after cerebral ischemia in vivo. In addition to the intracellular calcium deregulation, glutamate-induced cell death also involves mechanisms of oxidative stress and mitochondrial dysfunction. Therefore, we sought to investigate whether SK channel activation might also affect mechanisms of intrinsic death pathways induced by reactive oxygen species (ROS) such as hydrogen peroxide (H2O2). Exposure of immortalized hippocampal HT-22 cells to H2O2 imposed activation of a cascade of intracellular toxic events resulting in intracellular ROS production, mitochondrial loss of function, and ultimately cell death. Using a pharmacological approach to activate SK channels with CyPPA, we demonstrated a reduction of H2O2-mediated intracellular ROS production and cell death. Interestingly, CyPPA mediated neuroprotection in conditions of extracellular calcium and/or pyruvate depletion, pointing to a neuroprotective role of mitochondrial SK channels. Moreover, CyPPA partially inhibited H2O2-induced mitochondrial superoxide production, but did not prevent mitochondrial membrane depolarization. CyPPA treatment resulted in slight ATP depletion and a reduction of mitochondrial respiration/oxygen consumption. These findings postulate that SK channels mediate a protective effect by preventing neuronal death from subsequent oxidative stress through an adaptive metabolic response at the level of mitochondria. Therefore, SK channel activation may serve as a therapeutic target, where mitochondrial dysfunction and related mechanisms of oxidative stress contribute to progressive degeneration and death of neurons.
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg D-35032, Germany; Department of Neurology, University of Marburg, Marburg D-35043, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Richter
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg D-35032, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Nickel
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg D-35032, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Apel
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg D-35032, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kaas
authors.affiliation: Department of Neurology, University of Marburg, Marburg D-35043, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Dodel
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg D-35032, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Culmsee
authors.affiliation: Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg D-35032, Germany. Electronic address: dolga@staff.uni-marburg.de.
authors.forename: Amalia M
authors.initials: AM
authors.lastname: Dolga
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D004579:Electron Transport / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*
chemical_list: D051640:Small-Conductance Calcium-Activated Potassium Channels; D006861:Hydrogen Peroxide
keywords: CyPPA; HT-22 cells; Mitochondria; Oxidative stress; SK channels