Activation of BKCa Channels Mediates Hippocampal Neuronal Death After Reoxygenation and Reperfusion |
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Authors: | Ming Chen Hong-Yu Sun Ping Hu Chun-Fei Wang Bo-Xing Li Shu-Ji Li Jian-Jun Li Hui-Ying Tan Tian-Ming Gao |
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Institution: | 1. Department of Neurobiology, Southern Medical University, Guangzhou, 510515, China 2. Key Laboratory of Neuroplasticity of Guangdong Higher Education Institutes, Southern Medical University, Guangzhou, 510515, China 3. Department of Physiology, Southern Medical University, Guangzhou, 510515, China
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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 Ca2+-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 Ca2+. 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 Ca2+-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. |
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