Evidence map›Paper›PMID 25239140›Full record

ArticleCirculation research2014

Ankyrin-G coordinates intercalated disc signaling platform to regulate cardiac excitability in vivo.

Michael A Makara, Jerry Curran, Sean C Little, Hassan Musa, Iuliia Polina, Sakima A Smith, Patrick J Wright, Sathya D Unudurthi, Jed Snyder, Vann Bennett and 2 more

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

Article in Circulation research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.

0numbers the graph read from it
0cells of the map it votes in
77citing papers in PubMed
9.1field-weighted citation impact, top 1% 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

77 citing papers in PubMed, 114 citations in OpenAlex.

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17 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

12 authors at 1 institution in 1 country.

Michael A MakaraFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.).
Jerry CurranFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.).
Sean C LittleFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.).
Hassan MusaFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.).
Iuliia PolinaFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.).
Sakima A SmithFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.).
Patrick J WrightFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.).
Sathya D UnudurthiFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.).
Jed SnyderFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.).
Vann BennettFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.).
Thomas J HundFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.).
Peter J MohlerFrom The Dorothy M. Davis Heart & Lung Research Institute (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., S.D.U., J.S., T.J.H., P.J.M. ), Departments of Internal Medicine (S.A.S., P.J.M.), and Physiology and Cell Biology (M.A.M., J.C., S.C.L., H.M., I.P., S.A.S., P.J.W., P.J.M.), The Ohio State University Wexner Medical Center, Columbus; Department of Biomedical Engineering, The Ohio State University College of Engineering, Columbus (S.D.U., J.S., T.J.H.); and Howard Hughes Medical Institute, Department of Biochemistry, Duke University Medical Center, Durham, NC (V.B.). peter.mohler@osumc.edu.
The Ohio State University · US

Funding

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
Training in Congenital and Acquired Heart DiseaseT32HL098039 · NHLBI · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · PI GARG, VIDU, MOHLER, PETER J. · 2009 to 2019
$2.5M
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 HL083422NHLBI NIH HHS R01 HL084583NHLBI NIH HHS R01 HL114383NHLBI NIH HHS R01 HL114893NHLBI NIH HHS T32 HL098039
6 · The paper itself

Abstract

rationaleNav1.5 (SCN5A) is the primary cardiac voltage-gated Nav channel. Nav1.5 is critical for cardiac excitability and conduction, and human SCN5A mutations cause sinus node dysfunction, atrial fibrillation, conductional abnormalities, and ventricular arrhythmias. Further, defects in Nav1.5 regulation are linked with malignant arrhythmias associated with human heart failure. Consequently, therapies to target select Nav1.5 properties have remained at the forefront of cardiovascular medicine. However, despite years of investigation, the fundamental pathways governing Nav1.5 membrane targeting, assembly, and regulation are still largely undefined.

objectiveDefine the in vivo mechanisms underlying Nav1.5 membrane regulation. METHODS AND

resultsHere, we define the molecular basis of an Nav channel regulatory platform in heart. Using new cardiac-selective ankyrin-G(-/-) mice (conditional knock-out mouse), we report that ankyrin-G targets Nav1.5 and its regulatory protein calcium/calmodulin-dependent kinase II to the intercalated disc. Mechanistically, βIV-spectrin is requisite for ankyrin-dependent targeting of calcium/calmodulin-dependent kinase II-δ; however, βIV-spectrin is not essential for ankyrin-G expression. Ankyrin-G conditional knock-out mouse myocytes display decreased Nav1.5 expression/membrane localization and reduced INa associated with pronounced bradycardia, conduction abnormalities, and ventricular arrhythmia in response to Nav channel antagonists. Moreover, we report that ankyrin-G links Nav channels with broader intercalated disc signaling/structural nodes, as ankyrin-G loss results in reorganization of plakophilin-2 and lethal arrhythmias in response to β-adrenergic stimulation.

conclusionsOur findings provide the first in vivo data for the molecular pathway required for intercalated disc Nav1.5 targeting/regulation in heart. Further, these new data identify the basis of an in vivo cellular platform critical for membrane recruitment and regulation of Nav1.5.

Indexed as

Action PotentialsAnimalsAnkyrinsArrhythmias, CardiacCalcium-Calmodulin-Dependent Protein Kinase Type 2Cell MembraneMiceMyocytes, CardiacNAV1.5 Voltage-Gated Sodium ChannelPlakophilinsProtein BindingProtein TransportSignal TransductionSodium Channel BlockersSpectrinAnk3 protein, mouseAnkyrinsCalcium-Calmodulin-Dependent Protein Kinase Type 2NAV1.5 Voltage-Gated Sodium ChannelPlakophilinsScn5a protein, mouseSodium Channel BlockersSpectrinankyrinarrhythmia (mechanisms)cell biologymouse mutantNav1.5protein traffickingsodium channelstargeting

Identifiers

PMID25239140
PMCPMC4224970
OpenAlexW2165712235

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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.