Linked Life Data

15528464

Source:http://linkedlifedata.com/resource/pubmed/id/15528464

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2004-12-13
pubmed:abstractText
The KCNQ1-G589D gene mutation, associated with a long-QT syndrome, has been shown to disrupt yotiao-mediated targeting of protein kinase A and protein phosphatase-1 to the I(Ks) channel. To investigate how this defect may lead to ventricular arrhythmia during sympathetic stimulation, we use integrative computational models of beta-adrenergic signaling, myocyte excitation-contraction coupling, and action potential propagation in a rabbit ventricular wedge. Paradoxically, we find that the KCNQ1-G589D mutation alone does not prolong the QT interval. But when coupled with beta-adrenergic stimulation in a whole-cell model, the KCNQ1-G589D mutation induced QT prolongation and transient afterdepolarizations, known cellular mechanisms for arrhythmogenesis. These cellular mechanisms amplified tissue heterogeneities in a three-dimensional rabbit ventricular wedge model, elevating transmural dispersion of repolarization and creating other T-wave abnormalities on simulated electrocardiograms. Increasing heart rate protected both single myocyte and the coupled myocardium models from arrhythmic consequences. These findings suggest that the KCNQ1-G589D mutation disrupts a critical link between beta-adrenergic signaling and myocyte electrophysiology, creating both triggers of cardiac arrhythmia and a myocardial substrate vulnerable to such electrical disturbances.
pubmed:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Dec
pubmed:issn
1524-4571
pubmed:author
pubmed:issnType
Electronic
pubmed:day
10
pubmed:volume
95
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1216-24
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:15528464-Action Potentials, pubmed-meshheading:15528464-Adaptor Proteins, Signal Transducing, pubmed-meshheading:15528464-Adrenergic beta-1 Receptor Agonists, pubmed-meshheading:15528464-Amino Acid Substitution, pubmed-meshheading:15528464-Animals, pubmed-meshheading:15528464-Binding Sites, pubmed-meshheading:15528464-Computational Biology, pubmed-meshheading:15528464-Computer Simulation, pubmed-meshheading:15528464-Cytoskeletal Proteins, pubmed-meshheading:15528464-Electrocardiography, pubmed-meshheading:15528464-Heart Ventricles, pubmed-meshheading:15528464-Ion Transport, pubmed-meshheading:15528464-Isoproterenol, pubmed-meshheading:15528464-KCNQ Potassium Channels, pubmed-meshheading:15528464-KCNQ1 Potassium Channel, pubmed-meshheading:15528464-Long QT Syndrome, pubmed-meshheading:15528464-Models, Cardiovascular, pubmed-meshheading:15528464-Models, Molecular, pubmed-meshheading:15528464-Mutation, Missense, pubmed-meshheading:15528464-Myocardial Contraction, pubmed-meshheading:15528464-Myocytes, Cardiac, pubmed-meshheading:15528464-Point Mutation, pubmed-meshheading:15528464-Potassium, pubmed-meshheading:15528464-Potassium Channels, Voltage-Gated, pubmed-meshheading:15528464-Protein Binding, pubmed-meshheading:15528464-Protein Conformation, pubmed-meshheading:15528464-Protein Interaction Mapping, pubmed-meshheading:15528464-Rabbits, pubmed-meshheading:15528464-Receptors, Adrenergic, beta-1, pubmed-meshheading:15528464-Structure-Activity Relationship
pubmed:year
2004
pubmed:articleTitle
Proarrhythmic consequences of a KCNQ1 AKAP-binding domain mutation: computational models of whole cells and heterogeneous tissue.
pubmed:affiliation
Department of Bioengineering, Whitaker Institute of Biomedical Engineering, University of California San Diego, La Jolla92037-0412, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, Validation Studies