Activation of SK2 channels preserves ER Ca2+ homeostasis and protects against ER stress-induced cell death

Abstract

Alteration of endoplasmic reticulum (ER) Ca2+ homeostasis leads to excessive cytosolic Ca 2+ accumulation and delayed neuronal cell death in acute and chronic neurodegenerative disorders. While our recent studies established a protective role for SK channels against excessive intracellular Ca 2+ accumulation, their functional role in the ER has not been elucidated yet. We show here that SK2 channels are present in ER membranes of neuronal HT-22 cells, and that positive pharmacological modulation of SK2 channels with CyPPA protects against cell death induced by the ER stressors brefeldin A and tunicamycin. Calcium imaging of HT-22 neurons revealed that elevated cytosolic Ca 2+ levels and decreased ER Ca 2+ load during sustained ER stress could be largely prevented by SK2 channel activation. Interestingly, SK2 channel activation reduced the amount of the unfolded protein response transcription factor ATF4, but further enhanced the induction of CHOP. Using siRNA approaches we confirmed a detrimental role for ATF4 in ER stress, whereas CHOP regulation was dispensable for both, brefeldin A toxicity and CyPPA-mediated protection. Cell death induced by blocking Ca 2+ influx into the ER with the SERCA inhibitor thapsigargin was not prevented by CyPPA. Blocking the K + efflux via K + /H + exchangers with quinine inhibited CyPPA-mediated neuroprotection, suggesting an essential role of proton uptake and K + release in the SK channel-mediated neuroprotection. Our data demonstrate that ER SK2 channel activation preserves ER Ca 2+ uptake and retention which determines cell survival in conditions where sustained ER stress contributes to progressive neuronal death.

Altered NMDA receptor‐evoked intracellular Ca2+ dynamics in magnocellular neurosecretory neurons of hypertensive rats

“…), or subsequent to a cytoplasmic Ca 2+ overload (Richter et al . ). In fact, sustained NMDAR activation in hippocampal neurons was recently shown to contribute to ER stress via Ca 2+ overload (Dong et al .…”

“…Conversely, once established, ER stress affects ER Ca 2+ homeostasis, furthering in turn cytosolic Ca 2+ accumulation (Richter et al . ). Nevertheless, whether the enhanced tonic NMDAR activation that occurs in MNCs during hypertension (Zhang et al .…”

Review of toxicological effect of quantum dots on the liver

“…Similarly, CdSe/ZnS QDs caused an increase in the Ca 2+ concentration in L02 cells, which resulted in increasing mitochondrial ROS generation and activated NLRP3 inflammasomes (Lu et al, ). Current research suggests that the ER in organelles is mainly responsible for the dynamic balance of intracellular Ca 2+ ; harmful factors can trigger ER stress, leading to the breakdown of the Ca 2+ balance (Richter et al, ).…”

“…Ca 2+ can activate abundant, different, protein kinases involved in many biological processes such as cell proliferation, differentiation, and apoptosis. Elevated levels of Ca 2+ impaired mitochondrial membrane permeability, leading to the release of cytochrome c and induced apoptosis (Paesano et al, 2016;Richter et al, 2016). Some researchers have described that QDs could cause elevated intracellular Ca 2+ levels in HepG2 cells (Lu et al, 2016;Nguyen et al, 2015;Paesano et al, 2016 concentrations further increased ROS and aggravated oxidative stress (Nguyen et al, 2015).…”

“…harmful factors can trigger ER stress, leading to the breakdown of the Ca 2+ balance (Richter et al, 2016 . However, it does not get an in-depth exploration into the role of ER stress-induced apoptosis in the HepG2 cells by QDs.…”