title: Activation of SK2 channels preserves ER Ca²⁺ homeostasis and protects against ER stress-induced cell death.
abstract: Alteration of endoplasmic reticulum (ER) Ca(2+) 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.
authors.affiliation: Institute for Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Marburg, Germany.|Department of Neurology, Philipps-University Marburg, Marburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Richter
authors.affiliation: Department of Neurology, Philipps-University Marburg, Marburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Vidovic
authors.affiliation: Institute for Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Marburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Honrath
authors.affiliation: Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany.|Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Mahavadi
authors.affiliation: Department of Neurology, Philipps-University Marburg, Marburg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Dodel
authors.affiliation: Institute for Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Marburg, Germany.|Faculty of Mathematics and Natural Sciences, Molecular Pharmacology - Groningen Research Institute of Pharmacy, Groningen, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Dolga
authors.affiliation: Institute for Pharmacology and Clinical Pharmacy, Philipps-University Marburg, Marburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Culmsee
mesh_terms: D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006706:Homeostasis; D006801:Humans; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*
chemical_list: C496897:KCNN2 protein, human; D051640:Small-Conductance Calcium-Activated Potassium Channels; D002118:Calcium