Document Detail

Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death.
MedLine Citation:
PMID:  11334834     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: A variety of mutations in HERG, the major subunit of the rapidly activating component of the cardiac delayed rectifier I(Kr), have been found to underlie the congenital Long-QT syndrome, LQT2. LQT2 may give rise to severe arrhythmogenic phenotypes leading to sudden cardiac death. OBJECTIVE: We attempt to elucidate the mechanisms by which heterogeneous LQT2 genotypes can lead to prolongation of the action potential duration (APD) and consequently the QT interval on the ECG. METHODS: We develop Markovian models of wild-type (WT) and mutant I(Kr) channels and incorporate these models into a comprehensive model of the cardiac ventricular cell. RESULTS: Using this virtual transgenic cell model, we describe the effects of HERG mutations on the cardiac ventricular action potential (AP) and provide insight into the mechanism by which each defect results in a net loss of repolarizing current and prolongation of APD. CONCLUSIONS: This study demonstrates which mutations can prolong APD sufficiently to generate early afterdepolarizations (EADs), which may trigger life-threatening arrhythmias. The severity of the phenotype is shown to depend on the specific kinetic changes and how they affect I(Kr) during the time course of the action potential. Clarifying how defects in HERG can lead to impaired cellular electrophysiology can improve our understanding of the link between channel structure and cellular function.
C E Clancy; Y Rudy
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cardiovascular research     Volume:  50     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2001 May 
Date Detail:
Created Date:  2001-05-03     Completed Date:  2001-06-07     Revised Date:  2008-10-28    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  301-13     Citation Subset:  IM    
Cardiac Bioelectricity Research and Training Center, Department of Physiology and Biophysics, 509 Wickenden Building, Case Western Reserve University, Cleveland, Ohio 44106-7207, USA.
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MeSH Terms
Action Potentials / physiology
Cation Transport Proteins*
Computer Simulation
DNA-Binding Proteins*
Death, Sudden, Cardiac / etiology*
Ether-A-Go-Go Potassium Channels
Long QT Syndrome / complications,  genetics*
Markov Chains
Models, Cardiovascular
Potassium Channels / genetics*
Potassium Channels, Voltage-Gated*
Grant Support
Reg. No./Substance:
0/Cation Transport Proteins; 0/DNA-Binding Proteins; 0/ERG protein, human; 0/ERG1 potassium channel; 0/Ether-A-Go-Go Potassium Channels; 0/KCNH6 protein, human; 0/Potassium Channels; 0/Potassium Channels, Voltage-Gated; 0/Trans-Activators

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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