Evidence map›Paper›PMID 26187182›Full record

ArticleCirculation2015

Voltage-Gated Sodium Channel Phosphorylation at Ser571 Regulates Late Current, Arrhythmia, and Cardiac Function In Vivo.

Patric Glynn, Hassan Musa, Xiangqiong Wu, Sathya D Unudurthi, Sean Little, Lan Qian, Patrick J Wright, Przemyslaw B Radwanski, Sandor Gyorke, Peter J Mohler and 1 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.

0numbers the graph read from it
0cells of the map it votes in
79citing papers in PubMed
9.3field-weighted citation impact, top 2% of its field
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

79 citing papers in PubMed, 117 citations in OpenAlex.

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  4. Metabolic and Inflammatory Mechanisms Driving Atrial Fibrillation.Annual review of pharmacology and toxicology · 2026
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  8. The two-pore KAmerican journal of physiology. Heart and circulatory physiology · 2025
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  10. Gene therapy for atrial fibrillation.Journal of molecular and cellular cardiology · 2024
    Review
  11. Phosphorylation of cardiac sodium channel at Ser571 anticipates manifestations of the aging myopathy.American journal of physiology. Heart and circulatory physiology · 2024
    Article
  12. Review
  13. CaMKIIδ-dependent dysregulation of atrial NaFrontiers in pharmacology · 2024
    Article
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19 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

11 authors at 2 institutions in 1 country.

Patric GlynnFrom Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology & Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
Hassan MusaFrom Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology & Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
Xiangqiong WuFrom Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology & Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
Sathya D UnudurthiFrom Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology & Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
Sean LittleFrom Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology & Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
Lan QianFrom Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology & Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
Patrick J WrightFrom Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology & Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
Przemyslaw B RadwanskiFrom Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology & Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
Sandor GyorkeFrom Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology & Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
Peter J MohlerFrom Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology & Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.).
Thomas J HundFrom Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus (P.G., H.M., X.W., S.D.U., S.L., L.Q., P.J.W., P.B.R., S.G., P.J.M., T.J.H.); Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus (P.G., X.W., S.D.U., L.Q., T.J.H.); Departments of Physiology & Cell Biology (H.M., S.L., P.J.W., P.B.R., S.G., P.J.M.) and Internal Medicine (P.J.M., T.J.H.), The Ohio State University Wexner Medical Center, Columbus; and Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus (P.B.R.). Thomas.Hund@osumc.edu.
The Ohio State University Wexner Medical Center · USThe Ohio State University · US

Funding

CONTROLLED AND UNCONTROLLABLE CALCIUM RELEASE IN HEARTR01HL063043 · NHLBI · TEXAS TECH UNIVERSITY HEALTH SCIS CENTER · PI Sandor Gyorke · 1999 to 2026
$8.6M
Role of spectrin/ankyrin-G complex in myocyte signaling and cardiac excitabilityR01HL083422 · NHLBI · VANDERBILT UNIVERSITY · PI MOHLER, PETER J. · 2006 to 2016
$3.8M
Role of ankyrin-B in human arrhythmiaR01HL084583 · NHLBI · UNIVERSITY OF IOWA · PI MOHLER, PETER J. · 2006 to 2015
$3.4M
EHD proteins in cardiac membrane protein targeting and remodelingR01HL114383 · NHLBI · OHIO STATE UNIVERSITY · PI BOYDEN, PENELOPE ALTMAN, MOHLER, PETER J. · 2013 to 2016
$2.1M
CaMKII-dependent regulation of cardiac excitabilityR01HL114893 · NHLBI · OHIO STATE UNIVERSITY · PI HUND, THOMAS JEFFREY · 2012 to 2016
$1.9M
NHLBI NIH HHS HL083422NHLBI NIH HHS HL084583NHLBI NIH HHS HL114383NHLBI NIH HHS HL114893NHLBI NIH HHS R01 HL063043NHLBI NIH HHS R01 HL083422NHLBI NIH HHS R01 HL084583NHLBI NIH HHS R01 HL114383NHLBI NIH HHS R01 HL114893
6 · The paper itself

Abstract

backgroundVoltage-gated Na(+) channels (Nav) are essential for myocyte membrane excitability and cardiac function. Nav current (INa) is a large-amplitude, short-duration spike generated by rapid channel activation followed immediately by inactivation. However, even under normal conditions, a small late component of INa (INa,L) persists because of incomplete/failed inactivation of a subpopulation of channels. Notably, INa,L is directly linked with both congenital and acquired disease states. The multifunctional Ca(2+)/calmodulin-dependent kinase II (CaMKII) has been identified as an important activator of INa,L in disease. Several potential CaMKII phosphorylation sites have been discovered, including Ser571 in the Nav1.5 DI-DII linker, but the molecular mechanism underlying CaMKII-dependent regulation of INa,L in vivo remains unknown. METHODS AND

resultsTo determine the in vivo role of Ser571, 2 Scn5a knock-in mouse models were generated expressing either: (1) Nav1.5 with a phosphomimetic mutation at Ser571 (S571E), or (2) Nav1.5 with the phosphorylation site ablated (S571A). Electrophysiology studies revealed that Ser571 regulates INa,L but not other channel properties previously linked to CaMKII. Ser571-mediated increases in INa,L promote abnormal repolarization and intracellular Ca(2+) handling and increase susceptibility to arrhythmia at the cellular and animal level. Importantly, Ser571 is required for maladaptive remodeling and arrhythmias in response to pressure overload.

conclusionsOur data provide the first in vivo evidence for the molecular mechanism underlying CaMKII activation of the pathogenic INa,L. Relevant for improved rational design of potential therapies, our findings demonstrate that Ser571-dependent regulation of Nav1.5 specifically tunes INa,L without altering critical physiological components of the current.

Indexed as

AcetanilidesAction PotentialsAnimalsArrhythmias, CardiacCalciumCalcium-Calmodulin-Dependent Protein Kinase Type 2CardiomegalyConstrictionGene Knock-In TechniquesIon Channel GatingMaleMiceMice, Inbred C57BLNAV1.5 Voltage-Gated Sodium ChannelPhosphorylationPhosphoserineAcetanilidesCalciumCalcium-Calmodulin-Dependent Protein Kinase Type 2NAV1.5 Voltage-Gated Sodium ChannelPhosphoserinePiperazinesRanolazineScn5a protein, mouseSodiumSodium Channel Blockersaction potentialarrhythmias, cardiaccalcium-calmodulin-dependent protein kinase type 2ion channelsNa+ current

Identifiers

PMID26187182
PMCPMC4543581
OpenAlexW2166703440

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Read underepoch 390

Registered trials

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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.