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Published on: January 22, 2017
SK channel activation modulates mitochondrial respiration and attenuates neuronal HT-22 cell damage induced by H2O2
Maren Richter1, Catharina Nickel2, Lisa Apel2
1Institute of Pharmacology and Clinical Pharmacy, University of Marburg, Marburg D-35032, Germany; Department of Neurology, University of Marburg, Marburg D-35043, Germany.
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.
Insights
Small conductance calcium-activated potassium (SK) channels protect neurons from oxidative stress. Activating SK channels with CyPPA reduces reactive oxygen species and cell death, suggesting a therapeutic target for neurodegenerative diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Small conductance calcium-activated potassium (SK) channels are crucial in neuronal death pathways like glutamate excitotoxicity.
- Glutamate excitotoxicity involves calcium deregulation, oxidative stress, and mitochondrial dysfunction.
- The role of SK channels in oxidative stress-induced neuronal death remains unclear.
Purpose of the Study:
- To investigate if SK channel activation influences intrinsic neuronal death pathways triggered by reactive oxygen species (ROS).
- To explore the neuroprotective potential of SK channel activation against hydrogen peroxide (H2O2)-induced oxidative stress in HT-22 cells.
Main Methods:
- Pharmacological activation of SK channels using CyPPA in immortalized hippocampal HT-22 cells.
- Exposure of cells to hydrogen peroxide (H2O2) to induce oxidative stress and cell death.
- Assessment of intracellular ROS production, mitochondrial function (superoxide production, membrane potential), ATP levels, and oxygen consumption.
Main Results:
- CyPPA treatment reduced H2O2-induced intracellular ROS production and subsequent cell death.
- Neuroprotection by CyPPA was observed even with extracellular calcium or pyruvate depletion, suggesting mitochondrial SK channel involvement.
- CyPPA partially inhibited mitochondrial superoxide production but did not prevent membrane depolarization, indicating a complex interplay with mitochondrial function.
- CyPPA treatment led to mild ATP depletion and reduced mitochondrial respiration.
Conclusions:
- SK channel activation confers neuroprotection against oxidative stress, potentially via an adaptive metabolic response within mitochondria.
- Mitochondrial SK channels may play a protective role by modulating ROS production and cellular metabolism.
- Targeting SK channels could be a therapeutic strategy for neurodegenerative conditions involving mitochondrial dysfunction and oxidative stress.
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