Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.

Abstract

Excitation-contraction coupling in striated muscle requires proper communication of plasmalemmal voltage-activated Ca2+ channels and Ca2+ release channels on sarcoplasmic reticulum within junctional membrane complexes. Although previous studies revealed a loss of junctional membrane complexes and embryonic lethality in germ-line junctophilin-2 (JPH2) knockout mice, it has remained unclear whether JPH2 plays an essential role in junctional membrane complex formation and the Ca(2+)-induced Ca(2+) release process in the heart. Our recent work demonstrated loss-of-function mutations in JPH2 in patients with hypertrophic cardiomyopathy.To elucidate the role of JPH2 in the heart, we developed a novel approach to conditionally reduce JPH2 protein levels using RNA interference. Cardiac-specific JPH2 knockdown resulted in impaired cardiac contractility, which caused heart failure and increased mortality. JPH2 deficiency resulted in loss of excitation-contraction coupling gain, precipitated by a reduction in the number of junctional membrane complexes and increased variability in the plasmalemma-sarcoplasmic reticulum distance.Loss of JPH2 had profound effects on Ca2+ release channel inactivation, suggesting a novel functional role for JPH2 in regulating intracellular Ca2+ release channels in cardiac myocytes. Thus, our novel approach of cardiac-specific short hairpin RNA-mediated knockdown of junctophilin-2 has uncovered a critical role for junctophilin in intracellular Ca2+ release in the heart.

Type

Journal article

Department

Description

Provenance

Subjects

Cell Membrane, Intercellular Junctions, Animals, Mice, Transgenic, Mice, Knockout, Mice, Calcium Channels, Ryanodine Receptor Calcium Release Channel, Membrane Proteins, RNA, Small Interfering, Myocardial Contraction, Heart Failure, Gene Knockdown Techniques

Citation

Published Version (Please cite this version)

10.1161/CIRCULATIONAHA.110.006437

Publication Info

Van Oort, RJ, A Garbino, W Wang, SS Dixit, AP Landstrom, N Gaur, AC De Almeida, DG Skapura, et al. (2011). Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice. Circulation, 123(9). pp. 979–988. 10.1161/CIRCULATIONAHA.110.006437 Retrieved from https://hdl.handle.net/10161/20330.

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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, and short QT syndrome.  He also specializes in the evaluation of children following a cardiac arrest or after the sudden and unexplained death of a family member.  He has expertise in cardiovascular genetics and uses it to identify individuals in a family who may be at risk of a disease, even if all clinical testing is negative.  As a scientist, he is trained in genetics and cell biology.  He runs a research lab exploring the genetic and molecular causes of arrhythmias, sudden unexplained death syndromes, and heart muscle disease (cardiomyopathies).  He utilizes patient-derived induced pluripotent stem cells and genetic mouse models to identify the mechanisms of cardiovascular genetic disease with the goal of developing novel therapies.


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