Evidence map›Paper›PMID 26283144›Full record

ArticleCirculation. Arrhythmia and electrophysiology2015

Direct Measurement of Cardiac Na+ Channel Conformations Reveals Molecular Pathologies of Inherited Mutations.

Zoltan Varga, Wandi Zhu, Angela R Schubert, Jennifer L Pardieck, Arie Krumholz, Eric J Hsu, Mark A Zaydman, Jianmin Cui, Jonathan R Silva

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation. Arrhythmia and electrophysiology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.

0numbers the graph read from it
0cells of the map it votes in
28citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

28 citing papers in PubMed.

  1. Trial
  2. Article
  3. Article
  4. Calcium interaction with Nav1.5 via FGF12A and CaM binding.bioRxiv : the preprint server for biology · 2026
    Article
  5. Article
  6. Article
  7. Article
  8. Review
  9. Article
  10. Article
  11. Article
  12. Voltage sensor movements of CaProceedings of the National Academy of Sciences of the United States of America · 2021
    Article
  13. Review
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. A Molecularly Detailed NaJACC. Basic to translational science · 2019
    Article
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Zoltan VargaFrom the Department of Biomedical Engineering, Washington University in St. Louis, MO (Z.V., W.Z., A.R.S., J.L.P., A.K., E.J.H., M.A.Z., J.C., J.R.S.); and MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary (Z.V.).
Wandi ZhuFrom the Department of Biomedical Engineering, Washington University in St. Louis, MO (Z.V., W.Z., A.R.S., J.L.P., A.K., E.J.H., M.A.Z., J.C., J.R.S.); and MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary (Z.V.).
Angela R SchubertFrom the Department of Biomedical Engineering, Washington University in St. Louis, MO (Z.V., W.Z., A.R.S., J.L.P., A.K., E.J.H., M.A.Z., J.C., J.R.S.); and MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary (Z.V.).
Jennifer L PardieckFrom the Department of Biomedical Engineering, Washington University in St. Louis, MO (Z.V., W.Z., A.R.S., J.L.P., A.K., E.J.H., M.A.Z., J.C., J.R.S.); and MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary (Z.V.).
Arie KrumholzFrom the Department of Biomedical Engineering, Washington University in St. Louis, MO (Z.V., W.Z., A.R.S., J.L.P., A.K., E.J.H., M.A.Z., J.C., J.R.S.); and MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary (Z.V.).
Eric J HsuFrom the Department of Biomedical Engineering, Washington University in St. Louis, MO (Z.V., W.Z., A.R.S., J.L.P., A.K., E.J.H., M.A.Z., J.C., J.R.S.); and MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary (Z.V.).
Mark A ZaydmanFrom the Department of Biomedical Engineering, Washington University in St. Louis, MO (Z.V., W.Z., A.R.S., J.L.P., A.K., E.J.H., M.A.Z., J.C., J.R.S.); and MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary (Z.V.).
Jianmin CuiFrom the Department of Biomedical Engineering, Washington University in St. Louis, MO (Z.V., W.Z., A.R.S., J.L.P., A.K., E.J.H., M.A.Z., J.C., J.R.S.); and MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary (Z.V.).
Jonathan R SilvaFrom the Department of Biomedical Engineering, Washington University in St. Louis, MO (Z.V., W.Z., A.R.S., J.L.P., A.K., E.J.H., M.A.Z., J.C., J.R.S.); and MTA-DE-NAP B Ion Channel Structure-Function Research Group, RCMM, Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hungary (Z.V.). jonsilva@wustl.edu.

Funding

CARDIOVASCULAR SYSTEM--FUNCTION/REGULATION/PHARMACOLOGYT32HL007275 · NHLBI · WASHINGTON UNIVERSITY · PI NERBONNE, JEANNE M. · 1985 to 2013
$6.0M
Ca2+ Dependent K+ Channels: Allosteric GatingR01HL070393 · NHLBI · WASHINGTON UNIVERSITY · PI CUI, JIANMIN · 2002 to 2015
$4.9M
DEVELOPMENTAL CARDIOLOGY AND PULMONARY TRAINING PROGRAMT32HL007873 · NHLBI · WASHINGTON UNIVERSITY · PI MECHAM, ROBERT P. · 1998 to 2012
$3.6M
SUR1 (ABCC8) AND ATRIAL KATP CHANNELSR01HL095010 · NHLBI · WASHINGTON UNIVERSITY · PI NICHOLS, COLIN G · 2009 to 2017
$3.4M
Channels with KCNE Subunits: Conformational DynamicsR01HL105949 · NHLBI · BRANDEIS UNIVERSITY · PI GOLDSTEIN, STEVE A N · 2011 to 2015
$1.5M
SUBUNITS INTERACTION IN THE FUNCTION OF BK CHANNELSR01NS060706 · NINDS · WASHINGTON UNIVERSITY · PI CUI, JIANMIN · 2010 to 2013
$1.3M
NHLBI NIH HHS R01 HL070393NHLBI NIH HHS R01 HL095010NHLBI NIH HHS R01 HL105949NHLBI NIH HHS R01-HL70393NHLBI NIH HHS R01-HL95010NHLBI NIH HHS T32 HL007275NHLBI NIH HHS T32-HL007275NHLBI NIH HHS T32 HL007873NHLBI NIH HHS T32-HL007873NINDS NIH HHS R01 NS060706NINDS NIH HHS R01-NS060706
6 · The paper itself

Abstract

backgroundDysregulation of voltage-gated cardiac Na(+) channels (NaV1.5) by inherited mutations, disease-linked remodeling, and drugs causes arrhythmias. The molecular mechanisms whereby the NaV1.5 voltage-sensing domains (VSDs) are perturbed to pathologically or therapeutically modulate Na(+) current (INa) have not been specified. Our aim was to correlate INa kinetics with conformational changes within the 4 (DI-DIV) VSDs to define molecular mechanisms of NaV1.5 modulation. METHOD AND

resultsFour NaV1.5 constructs were created to track the voltage-dependent kinetics of conformational changes within each VSD, using voltage-clamp fluorometry. Each VSD displayed unique kinetics, consistent with distinct roles in determining INa. In particular, DIII-VSD deactivation kinetics were modulated by depolarizing pulses with durations in the intermediate time domain that modulates late INa. We then used the DII-VSD construct to probe the molecular pathology of 2 Brugada syndrome mutations (A735V and G752R). A735V shifted DII-VSD voltage dependence to depolarized potentials, whereas G752R significantly slowed DII-VSD kinetics. Both mutations slowed INa activation, although DII-VSD activation occurred at higher potentials (A735V) or at later times (G752R) than ionic current activation, indicating that the DII-VSD allosterically regulates the rate of INa activation and myocyte excitability.

conclusionsOur results reveal novel mechanisms whereby the NaV1.5 VSDs regulate channel activation and inactivation. The ability to distinguish distinct molecular mechanisms of proximal Brugada syndrome mutations demonstrates the potential of these methods to reveal how inherited mutations, post-translational modifications, and antiarrhythmic drugs alter NaV1.5 at the molecular level.

Indexed as

Brugada SyndromeGenetic Predisposition to DiseaseHumansIon Channel GatingKineticsMembrane PotentialsMutationPhenotypeProtein Processing, Post-TranslationalSodium ChannelsSodium ChannelsBrugada syndromefluorometryion channelsmutationsodium channels

Identifiers

PMID26283144
PMCPMC4618166

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.