title: SK2 channels are neuroprotective for ischemia-induced neuronal cell death.
abstract: In mouse hippocampal CA1 pyramidal neurons, the activity of synaptic small-conductance Ca(2+)-activated K(+) channels type 2 (SK2 channels) provides a negative feedback on N-methyl-D-aspartate receptors (NMDARs), reestablishing Mg(2+) block that reduces Ca(2+) influx. The well-established role of NMDARs in ischemia-induced excitotoxicity led us to test the neuroprotective effect of modulating SK2 channel activity following cerebral ischemia induced by cardiac arrest and cardiopulmonary resuscitation (CA/CPR). Administration of the SK channel positive modulator, 1-ethyl-benzimidazolinone (1-EBIO), significantly reduced CA1 neuron cell death and improved CA/CPR-induced cognitive outcome. Electrophysiological recordings showed that CA/CPR-induced ischemia caused delayed and sustained reduction of synaptic SK channel activity, and immunoelectron microscopy showed that this is associated with internalization of synaptic SK2 channels, which was prevented by 1-EBIO treatment. These results suggest that increasing SK2 channel activity, or preventing ischemia-induced loss of synaptic SK2 channels, are promising and novel approaches to neuroprotection following cerebral ischemia.
authors.affiliation: Vollum Institute, Oregon Health and Science University, Portland, Oregon 97201, USA.
authors.forename: Duane
authors.initials: D
authors.lastname: Allen
authors.forename: Shin
authors.initials: S
authors.lastname: Nakayama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kuroiwa
authors.forename: Takaaki
authors.initials: T
authors.lastname: Nakano
authors.forename: Julie
authors.initials: J
authors.lastname: Palmateer
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Kosaka
authors.forename: Carmen
authors.initials: C
authors.lastname: Ballesteros
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Chris T
authors.initials: CT
authors.lastname: Bond
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.forename: James
authors.initials: J
authors.lastname: Maylie
authors.forename: John P
authors.initials: JP
authors.lastname: Adelman
authors.forename: Paco S
authors.initials: PS
authors.lastname: Herson
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001562:Benzimidazoles / Q000494:pharmacology; D002545:Brain Ischemia / Q000473:pathology* / Q000523:psychology; D056547:CA1 Region, Hippocampal / Q000473:pathology; D016887:Cardiopulmonary Resuscitation; D016923:Cell Death; D006323:Heart Arrest / Q000150:complications / Q000473:pathology; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000473:pathology; D021641:Recognition, Psychology / Q000502:physiology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000502:physiology*; D013569:Synapses / Q000502:physiology / Q000648:ultrastructure
chemical_list: D001562:Benzimidazoles; C496898:Kcnn2 protein, mouse; D051640:Small-Conductance Calcium-Activated Potassium Channels; C102635:1-ethyl-2-benzimidazolinone