Neuronal Ca2+-activated K+ channels limit brain infarction and promote survival

Neuronal calcium-activated potassium channels of the BK type are activated by membrane depolarization and intracellular Ca(2+) ions. It has been suggested that these channels may play a key neuroprotective role during and after brain ischemia, but this hypothesis has so far not been tested by select...

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Bibliographic Details
Published in:PloS one 2010-12, Vol.5 (12), p.e15601
Main Authors: Liao, Yiliu, Kristiansen, Ase-Marit, Oksvold, Cecilie P, Tuvnes, Frode A, Gu, Ning, Rundén-Pran, Elise, Ruth, Peter, Sausbier, Matthias, Storm, Johan F
Format: Article
Language:eng ; nor
Subjects:
Action potential
Animals
Biology
Blood
Blood flow
Brain
Brain damage
Brain Infarction - pathology
Brain Infarction - therapy
Brain injury
Brain slice preparation
Calcium
Calcium (intracellular)
Calcium - chemistry
Calcium channels
Calcium Channels - metabolism
Calcium ions
Carotid arteries
Cell Survival
Cerebral blood flow
Cerebral Cortex - pathology
Cerebral infarction
Cerebrovascular Circulation
Channels
Chlorides
Depolarization
Doppler effect
Genotypes
Hippocampus
Homozygote
Hypoxia
Infarction
Ischemia
Kinases
Male
Medicine
Membrane potential
Mice
Mice, Inbred C57BL
Middle Cerebral Artery - pathology
Molecular biology
N-Methyl-D-aspartic acid
N-Methylaspartate - metabolism
Neurological diseases
Neurons - metabolism
Neuroprotection
Neurosciences
Neurotoxicity
Occlusion
Patch-Clamp Techniques
Pharmacology
Pharmacy
Physiology
Potassium
Potassium channels
Potassium channels (calcium-gated)
Potassium Channels - metabolism
Pyramidal cells
Reperfusion
Rodents
Stroke
Toxicology
Transmitters
Trends
Veins & arteries
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Summary:Neuronal calcium-activated potassium channels of the BK type are activated by membrane depolarization and intracellular Ca(2+) ions. It has been suggested that these channels may play a key neuroprotective role during and after brain ischemia, but this hypothesis has so far not been tested by selective BK-channel manipulations in vivo. To elucidate the in vivo contribution of neuronal BK channels in acute focal cerebral ischemia, we performed middle cerebral artery occlusion (MCAO) in mice lacking BK channels (homozygous mice lacking the BK channel alpha subunit, BK(-/-)). MCAO was performed in BK(-/-) and WT mice for 90 minutes followed by a 7-hour-reperfusion period. Coronal 1 mm thick sections were stained with 2,3,5-triphenyltetrazolium chloride to reveal the infarction area. We found that transient focal cerebral ischemia by MCAO produced larger infarct volume, more severe neurological deficits, and higher post-ischemic mortality in BK(-/-) mice compared to WT littermates. However, the regional cerebral blood flow was not significantly different between genotypes as measured by Laser Doppler (LD) flowmetry pre-ischemically, intra-ischemically, and post-ischemically, suggesting that the different impact of MCAO in BK(-/-) vs. WT was not due to vascular BK channels. Furthermore, when NMDA was injected intracerebrally in non-ischemic mice, NMDA-induced neurotoxicity was found to be larger in BK(-/-) mice compared to WT. Whole-cell patch clamp recordings from CA1 pyramidal cells in organotypic hippocampal slice cultures revealed that BK channels contribute to rapid action potential repolarization, as previously found in acute slices. When these cultures were exposed to ischemia-like conditions this induced significantly more neuronal death in BK(-/-) than in WT cultures. These results indicate that neuronal BK channels are important for protection against ischemic brain damage.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0015601