Reduced junctional Na+/Ca2+-exchanger activity contributes to sarcoplasmic reticulum Ca2+ leak in junctophilin-2-deficient mice.
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 articleSubject
Sarcoplasmic ReticulumCells, 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/10161/20314Published Version (Please cite this version)
10.1152/ajpheart.00413.2014Publication 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.
Collections
More Info
Show full item recordScholars@Duke
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,

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy
Rights for Collection: Scholarly Articles
Works are deposited here by their authors, and represent their research and opinions, not that of Duke University. Some materials and descriptions may include offensive content. More info