title: Blood-brain barrier KCa3.1 channels: evidence for a role in brain Na uptake and edema in ischemic stroke.
abstract: OBJECTIVE
  KCa3.1, a calcium-activated potassium channel, 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. However, the expression and physiological role of KCa3.1 in blood-brain barrier (BBB) endothelium has not been investigated. BBB endothelial cells transport Na(+) and Cl(-) from the blood into the brain transcellularly through the co-operation of multiple cotransporters, exchangers, pumps, and channels. In the early stages of cerebral ischemia, when the BBB is intact, edema formation occurs by processes involving increased BBB transcellular Na(+) transport. This study evaluated whether KCa3.1 is expressed on and participates in BBB ion transport.
  
  
  METHODS
  The expression of KCa3.1 on cultured cerebral microvascular endothelial cells, isolated microvessels, and brain sections was evaluated by Western blot and immunohistochemistry. Activity of KCa3.1 on cerebral microvascular endothelial cells was examined by K(+) flux assays and patch-clamp. Magnetic resonance spectroscopy and MRI were used to measure brain Na(+) uptake and edema formation in rats with focal ischemic stroke after TRAM-34 treatment.
  
  
  RESULTS
  KCa3.1 current and channel protein were identified on bovine cerebral microvascular endothelial cells and freshly isolated rat microvessels. In situ KCa3.1 expression on BBB endothelium was confirmed in rat and human brain sections. TRAM-34 treatment significantly reduced Na(+) uptake, and cytotoxic edema in the ischemic brain.
  
  
  CONCLUSIONS
  BBB endothelial cells exhibit KCa3.1 protein and activity and pharmacological blockade of KCa3.1 seems to provide an effective therapeutic approach for reducing cerebral edema formation in the first 3 hours of ischemic stroke.
authors.affiliation: From the Department of Pharmacology (Y.-J.C., D.P.J., H.W.) and Department of Physiology and Membrane Biology (B.K.W., N.Y., M.E.O.), University of California, Davis. ijchen@ucdavis.ucdavis.edu.
authors.forename: Yi-Je
authors.initials: YJ
authors.lastname: Chen
authors.affiliation: From the Department of Pharmacology (Y.-J.C., D.P.J., H.W.) and Department of Physiology and Membrane Biology (B.K.W., N.Y., M.E.O.), University of California, Davis.
authors.forename: Breanna K
authors.initials: BK
authors.lastname: Wallace
authors.affiliation: From the Department of Pharmacology (Y.-J.C., D.P.J., H.W.) and Department of Physiology and Membrane Biology (B.K.W., N.Y., M.E.O.), University of California, Davis.
authors.forename: Natalie
authors.initials: N
authors.lastname: Yuen
authors.affiliation: From the Department of Pharmacology (Y.-J.C., D.P.J., H.W.) and Department of Physiology and Membrane Biology (B.K.W., N.Y., M.E.O.), University of California, Davis.
authors.forename: David P
authors.initials: DP
authors.lastname: Jenkins
authors.affiliation: From the Department of Pharmacology (Y.-J.C., D.P.J., H.W.) and Department of Physiology and Membrane Biology (B.K.W., N.Y., M.E.O.), University of California, Davis.
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.affiliation: From the Department of Pharmacology (Y.-J.C., D.P.J., H.W.) and Department of Physiology and Membrane Biology (B.K.W., N.Y., M.E.O.), University of California, Davis.
authors.forename: Martha E
authors.initials: ME
authors.lastname: O'Donnell
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002417:Cattle; D038524:Diffusion Magnetic Resonance Imaging; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D012964:Sodium / Q000378:metabolism*; D020521:Stroke / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D011720:Pyrazoles; C411671:TRAM 34; D012964:Sodium
keywords: KCa3.1 protein, mouse; blood–brain barrier; brain edema; cerebral ischemia; stroke