title: Intracellular calcium attenuates late current conducted by mutant human cardiac sodium channels.
abstract: BACKGROUND
  Mutations of the cardiac voltage-gated sodium channel (SCN5A gene encoding voltage-gated sodium channel [NaV1.5]) cause congenital long-QT syndrome type 3 (LQT3). Most NaV1.5 mutations associated with LQT3 promote a mode of sodium channel gating in which some channels fail to inactivate, contributing to increased late sodium current (INaL), which is directly responsible for delayed repolarization and prolongation of the QT interval. LQT3 patients have highest risk of arrhythmia during sleep or during periods of slow heart rate. During exercise (high heart rate), there is elevated steady-state intracellular free calcium (Ca(2+)) concentration. We hypothesized that higher levels of intracellular Ca(2+) may lower arrhythmia risk in LQT3 subjects through effects on INaL.
  
  
  RESULTS
  We tested this idea by examining the effects of varying intracellular Ca(2+) concentrations on the level of INaL in cells expressing a typical LQT3 mutation, delKPQ, and another SCN5A mutation, R225P. We found that elevated intracellular Ca(2+) concentration significantly reduced INaL conducted by mutant channels but not wild-type channels. This attenuation of INaL in delKPQ expressing cells by Ca(2+) was not affected by the CaM kinase II inhibitor KN-93 but was partially attenuated by truncating the C-terminus of the channel.
  
  
  CONCLUSIONS
  We conclude that intracellular Ca(2+) contributes to the regulation of INaL conducted by NaV1.5 mutants and propose that, during excitation-contraction coupling, elevated intracellular Ca(2+) suppresses mutant channel INaL and protects cells from delayed repolarization. These findings offer a plausible explanation for the lower arrhythmia risk in LQT3 subjects during fast heart rates.
authors.affiliation: From the Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (F.P., A.L.G.); and Department of Medicine (F.P., J.D.K., A.L.G.) and Department of Pharmacology (T.M.B., A.L.G.), Vanderbilt University, Nashville, TN. franck.potet@northwestern.edu.
authors.forename: Franck
authors.initials: F
authors.lastname: Potet
authors.affiliation: From the Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (F.P., A.L.G.); and Department of Medicine (F.P., J.D.K., A.L.G.) and Department of Pharmacology (T.M.B., A.L.G.), Vanderbilt University, Nashville, TN.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Beckermann
authors.affiliation: From the Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (F.P., A.L.G.); and Department of Medicine (F.P., J.D.K., A.L.G.) and Department of Pharmacology (T.M.B., A.L.G.), Vanderbilt University, Nashville, TN.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Kunic
authors.affiliation: From the Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (F.P., A.L.G.); and Department of Medicine (F.P., J.D.K., A.L.G.) and Department of Pharmacology (T.M.B., A.L.G.), Vanderbilt University, Nashville, TN.
authors.forename: Alfred L
authors.initials: AL
authors.lastname: George
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D006801:Humans; D015640:Ion Channel Gating; D051379:Mice; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D018408:Patch-Clamp Techniques
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D004247:DNA; D002118:Calcium
keywords: Na+ current; NaV1.5 voltage-gated sodium channel; SCN5A protein; calcium; electrophysiology; human; long QT syndrome