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Reduced junctional Na+/Ca2+-exchanger activity contributes to sarcoplasmic reticulum Ca2+ leak in junctophilin-2-deficient mice.

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Date
2014-11
Authors
Wang, W
Landstrom, AP
Wang, Q
Munro, ML
Beavers, D
Ackerman, MJ
Soeller, C
Wehrens, XHT
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Abstract
Expression silencing of junctophilin-2 (JPH2) in mouse heart leads to ryanodine receptor type 2 (RyR2)-mediated sarcoplasmic reticulum (SR) Ca(2+) leak and rapid development of heart failure. The mechanism and physiological significance of JPH2 in regulating RyR2-mediated SR Ca(2+) leak remains elusive. We sought to elucidate the role of JPH2 in regulating RyR2-mediated SR Ca(2+) release in the setting of cardiac failure. Cardiac myocytes isolated from tamoxifen-inducible conditional knockdown mice of JPH2 (MCM-shJPH2) were subjected to confocal Ca(2+) imaging. MCM-shJPH2 cardiomyocytes exhibited an increased spark frequency width with altered spark morphology, which caused increased SR Ca(2+) leakage. Single channel studies identified an increased RyR2 open probability in MCM-shJPH2 mice. The increase in spark frequency and width was observed only in MCM-shJPH2 and not found in mice with increased RyR2 open probability with native JPH2 expression. Na(+)/Ca(2+)-exchanger (NCX) activity was reduced by 50% in MCM-shJPH2 with no detectable change in NCX expression. Additionally, 50% inhibition of NCX through Cd(2+) administration alone was sufficient to increase spark width in myocytes obtained from wild-type mice. Additionally, superresolution analysis of RyR2 and NCX colocalization showed a reduced overlap between RyR2 and NCX in MCM-shJPH2 mice. In conclusion, decreased JPH2 expression causes increased SR Ca(2+) leakage by directly increasing open probability of RyR2 and by indirectly reducing junctional NCX activity through increased dyadic cleft Ca(2+). This demonstrates two novel and independent cellular mechanisms by which JPH2 regulates RyR2-mediated SR Ca(2+) leak and heart failure development.
Type
Journal article
Subject
Sarcoplasmic Reticulum
Cells, Cultured
Myocytes, Cardiac
Animals
Mice, Inbred C57BL
Mice
Cadmium
Ryanodine Receptor Calcium Release Channel
Sodium-Calcium Exchanger
Muscle Proteins
Membrane Proteins
Ion Channel Gating
Calcium Signaling
Gene Deletion
Heart Failure
Permalink
https://hdl.handle.net/10161/20314
Published Version (Please cite this version)
10.1152/ajpheart.00413.2014
Publication Info
Wang, W; Landstrom, AP; Wang, Q; Munro, ML; Beavers, D; Ackerman, MJ; ... Wehrens, XHT (2014). Reduced junctional Na+/Ca2+-exchanger activity contributes to sarcoplasmic reticulum Ca2+ leak in junctophilin-2-deficient mice. American journal of physiology. Heart and circulatory physiology, 307(9). pp. H1317-H1326. 10.1152/ajpheart.00413.2014. Retrieved from https://hdl.handle.net/10161/20314.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Landstrom

Andrew Paul Landstrom

Associate Professor of Pediatrics
Dr. Landstrom is a physician scientist who specializes in the care of children and young adults with arrhythmias, heritable cardiovascular diseases, and sudden unexplained death syndromes. As a clinician, he is trained in pediatric cardiology with a focus on arrhythmias and genetic diseases of the heart.  He specializes in caring for patients with heritable arrhythmia (channelopathies) such as long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia,
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