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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
2
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pubmed:dateCreated |
2009-6-29
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pubmed:abstractText |
Long QT syndrome variant 3 (LQT-3) is a channelopathy in which mutations in SCN5A, the gene coding for the primary heart Na(+) channel alpha subunit, disrupt inactivation to elevate the risk of mutation carriers for arrhythmias that are thought to be calcium (Ca(2+))-dependent. Spontaneous arrhythmogenic diastolic activity has been reported in myocytes isolated from mice harboring the well-characterized Delta KPQ LQT-3 mutation but the link to altered Ca(2+) cycling related to mutant Na(+) channel activity has not previously been demonstrated. Here we have investigated the relationship between elevated sarcoplasmic reticulum (SR) Ca(2+) load and induction of spontaneous diastolic inward current (I(TI)) in myocytes expressing Delta KPQ Na(+) channels, and tested the sensitivity of both to the antianginal compound ranolazine. We combined whole-cell patch clamp measurements, imaging of intracellular Ca(2+), and measurement of SR Ca(2+) content using a caffeine dump methodology. We compared the Ca(2+) content of Delta KPQ(+/-) myocytes displaying I(TI) to those without spontaneous diastolic activity and found that I(TI) induction correlates with higher sarcoplasmic reticulum (SR) Ca(2+). Both spontaneous diastolic I(TI) and underlying Ca(2+) waves are inhibited by ranolazine at concentrations that preferentially target I(NaL) during prolonged depolarization. Furthermore, ranolazine I(TI) inhibition is accompanied by a small but significant decrease in SR Ca(2+) content. Our results provide the first direct evidence that induction of diastolic transient inward current (I(TI)) in Delta KPQ(+/-) myocytes occurs under conditions of elevated SR Ca(2+) load.
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pubmed:grant |
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pubmed:commentsCorrections |
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http://linkedlifedata.com/resource/pubmed/commentcorrection/19371746-9826602
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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 |
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
1095-8584
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:volume |
47
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
326-34
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pubmed:dateRevised |
2010-12-3
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pubmed:meshHeading |
pubmed-meshheading:19371746-Acetanilides,
pubmed-meshheading:19371746-Animals,
pubmed-meshheading:19371746-Calcium,
pubmed-meshheading:19371746-Calcium Signaling,
pubmed-meshheading:19371746-Diastole,
pubmed-meshheading:19371746-Dose-Response Relationship, Drug,
pubmed-meshheading:19371746-Ion Channel Gating,
pubmed-meshheading:19371746-Long QT Syndrome,
pubmed-meshheading:19371746-Mice,
pubmed-meshheading:19371746-Mutation,
pubmed-meshheading:19371746-Myocytes, Cardiac,
pubmed-meshheading:19371746-Piperazines
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pubmed:year |
2009
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pubmed:articleTitle |
Diastolic transient inward current in long QT syndrome type 3 is caused by Ca2+ overload and inhibited by ranolazine.
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pubmed:affiliation |
Department of Pharmacology, Columbia University College of Physicians and Surgeons, 630 West 168th St., New York, NY 10032, USA.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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