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Potassium Channels in Ischemic Stroke
Author(s) -
Chen YiJe Jay,
Nguyen Hai M,
O'Donnell Martha E.,
Wulff Heike
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1224.19
Subject(s) - microglia , medicine , potassium channel , cerebral edema , ischemia , stroke (engine) , edema , blood–brain barrier , pharmacology , inflammation , central nervous system , mechanical engineering , engineering
On average, a stroke occurs every 40s in the United States and 87% of these cases are ischemic strokes. In the acute phase, cerebral edema is a major cause of neuronal death, and then activated microglia/macrophages significantly contribute to the secondary inflammatory damage later in ischemic stroke. Neither the physiological or pathological roles of potassium channels in ischemic stroke have been systematically explored. Our studies reveal that potassium channels are important in cerebral edema formation and microglia/macrophage activation. KCa3.1, a calcium‐activated potassium channel, physiologically regulates ion and fluid secretion in the lung and gastrointestinal tract. It is also expressed on vascular endothelium where it participates in blood pressure regulation. Our recent study of the expression and physiological role of KCa3.1 in blood–brain barrier (BBB) endothelium found that BBB endothelial cells exhibit KCa3.1 protein and activity facilitating Na + transportation from the blood into the brain transcellularly through the co‐operation of multiple cotransporters, exchangers, pumps, and channels in normal physiological conditions and the early stages of cerebral ischemia, when the BBB is still intact. Pharmacological blockade with KCa3.1 blocker, TRAM‐34, significantly reduced Na + uptake, and cytotoxic edema measured by MRI in the ischemic rat brain with permanent middle cerebral artery occlusion (MCAO) in the first 3 hours of ischemic stroke. (Chen et el. 2015 Stroke 46:237.) Together with the voltage‐gated potassium channel Kv1.3, KCa3.1 also regulates membrane potential and Ca 2+ signaling in microglia and monocyte‐derived macrophages. We recently evaluated acute isolated microglia/macrophage from mice subjected to MCAO with eight days of reperfusion. Microglia from the infarcted area exhibited higher densities of K + currents with the biophysical and pharmacological properties of Kv1.3, KCa3.1 and Kir2.1 than microglia from non‐infarcted control brains. Similarly, immunohistochemistry on human infarcts showed strong Kv1.3 and KCa3.1 immunoreactivity on activated microglia/macrophages. Pharmacological inhibition or genetic deletion of KCa3.1 resulted in significantly smaller infarct areas on day‐8 after MCAO and improved neurological deficits. Both manipulations reduced microglia/macrophage activation and brain cytokine levels. (Chen et al. 2015 JCBFM; epub) In summary, K + channels can be a potential pharmacological target for ischemic stroke to slow down cerebral edema formation and reduce the secondary inflammatory damage from activated microglia/macrophage. Support or Funding Information Supported by AHA & NIHGM