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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
10
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pubmed:dateCreated |
2003-11-17
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pubmed:abstractText |
KCNQ1 alpha-subunits coassemble with KCNE1 beta-subunits to form channels that conduct the slow delayed rectifier K+ current (IKs) important for repolarization of the cardiac action potential. Mutations in KCNQ1 reduce IKs and cause long-QT syndrome, a disorder of ventricular repolarization that predisposes affected individuals to arrhythmia and sudden death. Current therapy for long-QT syndrome is inadequate. R-L3 is a benzodiazepine that activates IKs and has the potential to provide gene-specific therapy. In the present study, we characterize the molecular determinants of R-L3 interaction with KCNQ1 channels, use computer modeling to propose a mechanism for drug-induced changes in channel gating, and determine its effect on several long-QT syndrome-associated mutant KCNQ1 channels heterologously expressed in Xenopus oocytes. Scanning mutagenesis combined with voltage-clamp analysis indicated that R-L3 interacts with specific residues located in the 5th and 6th transmembrane domains of KCNQ1 subunits. Most KCNQ1 mutant channels responded to R-L3 similarly to wild-type channels, but one mutant channel (G306R) was insensitive to R-L3 possibly because it disrupted a key component of the drug-binding site.
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pubmed:grant |
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anti-Arrhythmia Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Benzodiazepines,
http://linkedlifedata.com/resource/pubmed/chemical/KCNQ Potassium Channels,
http://linkedlifedata.com/resource/pubmed/chemical/KCNQ1 Potassium Channel,
http://linkedlifedata.com/resource/pubmed/chemical/KCNQ1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/L 364373,
http://linkedlifedata.com/resource/pubmed/chemical/Potassium Channels,
http://linkedlifedata.com/resource/pubmed/chemical/Potassium Channels, Voltage-Gated,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Subunits
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1524-4571
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
14
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pubmed:volume |
93
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
941-7
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pubmed:dateRevised |
2008-11-21
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pubmed:meshHeading |
pubmed-meshheading:14576198-Amino Acid Substitution,
pubmed-meshheading:14576198-Animals,
pubmed-meshheading:14576198-Anti-Arrhythmia Agents,
pubmed-meshheading:14576198-Arrhythmias, Cardiac,
pubmed-meshheading:14576198-Benzodiazepines,
pubmed-meshheading:14576198-Binding Sites,
pubmed-meshheading:14576198-Humans,
pubmed-meshheading:14576198-Ion Channel Gating,
pubmed-meshheading:14576198-KCNQ Potassium Channels,
pubmed-meshheading:14576198-KCNQ1 Potassium Channel,
pubmed-meshheading:14576198-Long QT Syndrome,
pubmed-meshheading:14576198-Microinjections,
pubmed-meshheading:14576198-Mutagenesis, Site-Directed,
pubmed-meshheading:14576198-Mutation,
pubmed-meshheading:14576198-Oocytes,
pubmed-meshheading:14576198-Patch-Clamp Techniques,
pubmed-meshheading:14576198-Potassium Channels,
pubmed-meshheading:14576198-Potassium Channels, Voltage-Gated,
pubmed-meshheading:14576198-Protein Structure, Tertiary,
pubmed-meshheading:14576198-Protein Subunits,
pubmed-meshheading:14576198-Xenopus
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pubmed:year |
2003
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pubmed:articleTitle |
Pharmacological activation of normal and arrhythmia-associated mutant KCNQ1 potassium channels.
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pubmed:affiliation |
Department of Physiology and Eccles Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah 84112, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, P.H.S.,
Research Support, Non-U.S. Gov't
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