title: Activation of BKca channels mediates hippocampal neuronal death after reoxygenation and reperfusion.
abstract: Excessive K(+) efflux promotes central neuronal apoptosis; however, the type of potassium channel that mediates K(+) efflux in response to different apoptosis-inducing stimuli is still unknown. It is hypothesized that the activation of large-conductance Ca(2+)-activated K(+) channels (BKCa) mediates hypoxia/reoxygenation (H/R)- and ischemia/reperfusion (I/R)-induced neuronal apoptosis. Rat hippocampal neuronal cultures underwent apoptosis after reoxygenation, as assessed by morphologic observation, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and caspase-3 activation. Single-channel recordings revealed upregulation of BKCa channel activity 6 h after reoxygenation, which might be caused by elevated cytosolic Ca(2+). The K(+) ionophore valinomycin and the BKCa channel opener NS1619 induced neuronal apoptosis. Transfection of the BKCa channel α subunit into Chinese hamster ovary (CHO-K1) cells, which do not express endogenous K(+) channels, or into neurons will induce cell apoptosis, indicating that the opening of the BKCa channel serves as a pivotal event in mediating cell apoptosis. The specific BKCa channel blockers charybdotoxin and iberiotoxin and the nonselective K(+) channel blocker tetraethylammonium at concentrations more specific to the BKCa channel were neuroprotective. The A-type potassium channel blocker 4-aminopyridine and apamin, a small-conductance Ca(2+)-activated K(+) channel blocker, were not protective. This result suggests the involvement of the BKCa channel in H/R-induced apoptosis. Similarly, specific BKCa channel blockers also showed neuroprotection in neurons subjected to oxygen-glucose deprivation/reoxygenation or animals subjected to forebrain ischemia-reperfusion. These results demonstrate that the over-activity of BKCa channels mediates hippocampal neuronal damage induced by H/R in vitro and I/R in vivo.
authors: Department of Neurobiology, Southern Medical University, Guangzhou, 510515, China.
authors: Ming
authors: M
authors: Chen
authors: Hong-Yu
authors: HY
authors: Sun
authors: Ping
authors: P
authors: Hu
authors: Chun-Fei
authors: CF
authors: Wang
authors: Bo-Xing
authors: BX
authors: Li
authors: Shu-Ji
authors: SJ
authors: Li
authors: Jian-Jun
authors: JJ
authors: Li
authors: Hui-Ying
authors: HY
authors: Tan
authors: Tian-Ming
authors: TM
authors: Gao
mesh_terms: D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D006624:Hippocampus / Q000473:pathology*; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D002546:Ischemic Attack, Transient / Q000473:pathology; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D010100:Oxygen / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D015424:Reperfusion
chemical_list: C494842:Kcnma1 protein, rat; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D053148:Caspase 3; D005947:Glucose; D010100:Oxygen; D002118:Calcium
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