| Bilirubin oxidation end products directly alter K+ channels important in the regulation of vascular tone. | |
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MedLine Citation:
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PMID: 20424637 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The exact etiology of delayed cerebral vasospasm following cerebral hemorrhage is not clear, but a family of compounds termed 'bilirubin oxidation end products (BOXes)' derived from heme has been implicated. As proper regulation of vascular smooth muscle tone involves large-conductance Ca(2+)- and voltage-dependent Slo1 K(+) (BK, maxiK, K(Ca)1.1) channels, we examined whether BOXes altered functional properties of the channel. Electrophysiological measurements of Slo1 channels heterologously expressed in a human cell line and of native mouse BK channels in isolated cerebral myocytes showed that BOXes markedly diminished open probability. Biophysically, BOXes specifically stabilized the conformations of the channel with its ion conduction gate closed. The results of chemical amino-acid modifications and molecular mutagenesis together suggest that two specific lysine residues in the structural element linking the transmembrane ion-permeation domain to the carboxyl cytosolic domain of the Slo1 channel are critical in determining the sensitivity of the channel to BOXes. Inhibition of Slo1 BK channels by BOXes may contribute to the development of delayed cerebral vasospasm following brain hemorrhage. |
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Authors:
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Shangwei Hou; Rong Xu; Joseph F Clark; William L Wurster; Stefan H Heinemann; Toshinori Hoshi |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-04-28 |
Journal Detail:
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Title: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Volume: 31 ISSN: 1559-7016 ISO Abbreviation: J. Cereb. Blood Flow Metab. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-04 Completed Date: 2011-02-03 Revised Date: 2012-01-04 |
Medline Journal Info:
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Nlm Unique ID: 8112566 Medline TA: J Cereb Blood Flow Metab Country: United States |
Other Details:
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Languages: eng Pagination: 102-12 Citation Subset: IM |
Affiliation:
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Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Algorithms Amino Acid Sequence Animals Basilar Artery / drug effects, metabolism Bilirubin / cerebrospinal fluid, metabolism, physiology* Cerebrovascular Circulation / physiology* Electrophysiological Phenomena Humans Kinetics Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / drug effects, metabolism, physiology* Mice Mice, Inbred C57BL Molecular Sequence Data Muscle Tonus / physiology Muscle, Smooth, Vascular / physiology* Oxidation-Reduction Patch-Clamp Techniques Potassium Channel Blockers / pharmacology Vasospasm, Intracranial / physiopathology |
| Grant Support | |
ID/Acronym/Agency:
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GM057654/GM/NIGMS NIH HHS; NS050569/NS/NINDS NIH HHS; R01 GM057654-13/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/KCNMA1 protein, human; 0/Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; 0/Potassium Channel Blockers; 635-65-4/Bilirubin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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