Document Detail

Y1767C, a novel SCN5A mutation, induces a persistent Na+ current and potentiates ranolazine inhibition of Nav1.5 channels.
MedLine Citation:
PMID:  21076026     Owner:  NLM     Status:  MEDLINE    
Long QT syndrome type 3 (LQT3) has been traced to mutations of the cardiac Na(+) channel (Na(v)1.5) that produce persistent Na(+) currents leading to delayed ventricular repolarization and torsades de pointes. We performed mutational analyses of patients suffering from LQTS and characterized the biophysical properties of the mutations that we uncovered. One LQT3 patient carried a mutation in the SCN5A gene in which the cysteine was substituted for a highly conserved tyrosine (Y1767C) located near the cytoplasmic entrance of the Na(v)1.5 channel pore. The wild-type and mutant channels were transiently expressed in tsA201 cells, and Na(+) currents were recorded using the patch-clamp technique. The Y1767C channel produced a persistent Na(+) current, more rapid inactivation, faster recovery from inactivation, and an increased window current. The persistent Na(+) current of the Y1767C channel was blocked by ranolazine but not by many class I antiarrhythmic drugs. The incomplete inactivation, along with the persistent activation of Na(+) channels caused by an overlap of voltage-dependent activation and inactivation, known as window currents, appeared to contribute to the LQTS phenotype in this patient. The blocking effect of ranolazine on the persistent Na(+) current suggested that ranolazine may be an effective therapeutic treatment for patients with this mutation. Our data also revealed the unique role for the Y1767 residue in inactivating and forming the intracellular pore of the Na(v)1.5 channel.
Hai Huang; Silvia G Priori; Carlo Napolitano; Michael E O'Leary; Mohamed Chahine
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-12
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  300     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-04     Completed Date:  2011-01-28     Revised Date:  2014-09-17    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H288-99     Citation Subset:  IM    
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MeSH Terms
Acetanilides / pharmacology*
DNA Mutational Analysis
Enzyme Inhibitors / pharmacology
Ion Channel Gating / drug effects*,  genetics*
Long QT Syndrome / genetics*,  metabolism
Muscle Proteins / genetics*,  metabolism*
NAV1.5 Voltage-Gated Sodium Channel
Piperazines / pharmacology*
Sodium Channels / genetics*,  metabolism*
Grant Support
MT-13181//Canadian Institutes of Health Research; R01 GM078244/GM/NIGMS NIH HHS; R01 GM078244-05/GM/NIGMS NIH HHS
Reg. No./Substance:
0/Acetanilides; 0/Enzyme Inhibitors; 0/Muscle Proteins; 0/NAV1.5 Voltage-Gated Sodium Channel; 0/Piperazines; 0/SCN5A protein, human; 0/Sodium Channels; 110445-25-5/ranolazine
Comment In:
Am J Physiol Heart Circ Physiol. 2011 Mar;300(3):H716-7   [PMID:  21193585 ]

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

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