title: Activation of large-conductance Ca(2+)-activated K(+) channels inhibits glutamate-induced oxidative stress through attenuating ER stress and mitochondrial dysfunction.
abstract: Large-conductance Ca(2+)-activated K(+) channels (BK channels) are widely expressed throughout the vertebrate nervous system, and are involved in the regulation of neurotransmitter release and neuronal excitability. Here, the neuroprotective effects of NS11021, a selective and chemically unrelated BK channel activator, and potential molecular mechanism involved have been studied in rat cortical neurons exposed to glutamate in vitro. Pretreatment with NS11021 significantly inhibited the loss of neuronal viability, LDH release and neuronal apoptosis in a dose-dependent manner. All these protective effects were fully antagonized by the BK-channel inhibitor paxilline. NS11021-induced neuroprotection was associated with reduced oxidative stress, as evidenced by decreased reactive oxygen species (ROS) generation, lipid peroxidation and preserved activity of antioxidant enzymes. Moreover, NS11021 significantly attenuated the glutamate-induced endoplasmic reticulum (ER) calcium release and activation of ER stress markers, including glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and caspase-12. Pretreatment with NS11021 also mitigated the mitochondrial membrane potential (MMP) collapse, cytochrome c release, and preserved mitochondrial Ca(2+) buffering capacity and ATP synthesis after glutamate exposure. Taken together, these results suggest that activation of BK channels via NS11021 protects cortical neurons against glutamate-induced excitatory damage, which may be dependent on the inhibition of ER stress and preservation of mitochondrial dysfunction.
authors.affiliation: Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, 76 Yanta West Road, Xi'an, Shaanxi 710061, China; Department of Pediatrics of The Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of The School of Medicine Xi'an Jiaotong University, Xi'an, Shaanxi 710068, China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Yan
authors.affiliation: Department of Pediatrics of The Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of The School of Medicine Xi'an Jiaotong University, Xi'an, Shaanxi 710068, China.
authors.forename: Xiang-Yang
authors.initials: XY
authors.lastname: Guo
authors.affiliation: Department of Pediatrics of The Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of The School of Medicine Xi'an Jiaotong University, Xi'an, Shaanxi 710068, China.
authors.forename: Fu-Yong
authors.initials: FY
authors.lastname: Jiao
authors.affiliation: The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yanta West Road, Xi'an, Shaanxi 710061, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, 76 Yanta West Road, Xi'an, Shaanxi 710061, China. Electronic address: liuyong5599_xjtu@126.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000187:drug effects / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C524410:1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-bromo-2-(1H-tetrazol-5-yl)phenyl)thiourea; D018696:Neuroprotective Agents; D024681:Potassium Channels, Calcium-Activated; D013777:Tetrazoles; D018698:Glutamic Acid; D013890:Thiourea; D002118:Calcium
keywords: BK channels; ER stress; Mitochondrial dysfunction; Neuroprotection; Oxidative stress