PMID- 26022185
OWN - NLM
STAT- MEDLINE
DCOM- 20151103
LR  - 20181113
IS  - 1941-3084 (Electronic)
IS  - 1941-3149 (Print)
IS  - 1941-3084 (Linking)
VI  - 8
IP  - 4
DP  - 2015 Aug
TI  - Intracellular calcium attenuates late current conducted by mutant human cardiac 
      sodium channels.
PG  - 933-41
LID - 10.1161/CIRCEP.115.002760 [doi]
AB  - 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. METHODS AND 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.
CI  - (c) 2015 American Heart Association, Inc.
FAU - Potet, Franck
AU  - Potet F
AD  - 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.
FAU - Beckermann, Thomas M
AU  - Beckermann TM
AD  - 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.
FAU - Kunic, Jennifer D
AU  - Kunic JD
AD  - 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.
FAU - George, Alfred L Jr
AU  - George AL Jr
AD  - 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.
LA  - eng
GR  - R01 HL083374/HL/NHLBI NIH HHS/United States
GR  - HL083374/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150528
PL  - United States
TA  - Circ Arrhythm Electrophysiol
JT  - Circulation. Arrhythmia and electrophysiology
JID - 101474365
RN  - 0 (NAV1.5 Voltage-Gated Sodium Channel)
RN  - 9007-49-2 (DNA)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Arrhythmias, Cardiac/*genetics/metabolism
MH  - Calcium/*metabolism
MH  - Cells, Cultured
MH  - DNA/*genetics
MH  - DNA Mutational Analysis
MH  - Disease Models, Animal
MH  - Humans
MH  - Ion Channel Gating
MH  - Mice
MH  - *Mutation
MH  - Myocytes, Cardiac/*metabolism/pathology
MH  - NAV1.5 Voltage-Gated Sodium Channel/*genetics/metabolism
MH  - Patch-Clamp Techniques
PMC - PMC4545406
MID - NIHMS699130
OTO - NOTNLM
OT  - Na+ current
OT  - NaV1.5 voltage-gated sodium channel
OT  - SCN5A protein
OT  - calcium
OT  - electrophysiology
OT  - human
OT  - long QT syndrome
COIS- Conflict of Interest Disclosures: None.
EDAT- 2015/05/30 06:00
MHDA- 2015/11/04 06:00
PMCR- 2016/08/01
CRDT- 2015/05/30 06:00
PHST- 2014/01/09 00:00 [received]
PHST- 2015/05/07 00:00 [accepted]
PHST- 2015/05/30 06:00 [entrez]
PHST- 2015/05/30 06:00 [pubmed]
PHST- 2015/11/04 06:00 [medline]
PHST- 2016/08/01 00:00 [pmc-release]
AID - CIRCEP.115.002760 [pii]
AID - 10.1161/CIRCEP.115.002760 [doi]
PST - ppublish
SO  - Circ Arrhythm Electrophysiol. 2015 Aug;8(4):933-41. doi: 
      10.1161/CIRCEP.115.002760. Epub 2015 May 28.