Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.
| dc.contributor.author | Van Oort, RJ | |
| dc.contributor.author | Garbino, A | |
| dc.contributor.author | Wang, W | |
| dc.contributor.author | Dixit, SS | |
| dc.contributor.author | Landstrom, AP | |
| dc.contributor.author | Gaur, N | |
| dc.contributor.author | De Almeida, AC | |
| dc.contributor.author | Skapura, DG | |
| dc.contributor.author | Rudy, Y | |
| dc.contributor.author | Burns, AR | |
| dc.contributor.author | Ackerman, MJ | |
| dc.contributor.author | Wehrens, XHT | |
| dc.date.accessioned | 2020-04-01T13:44:24Z | |
| dc.date.available | 2020-04-01T13:44:24Z | |
| dc.date.issued | 2011-03 | |
| dc.date.updated | 2020-04-01T13:44:18Z | |
| dc.description.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. | |
| dc.identifier | CIRCULATIONAHA.110.006437 | |
| dc.identifier.issn | 0009-7322 | |
| dc.identifier.issn | 1524-4539 | |
| dc.identifier.uri | ||
| dc.language | eng | |
| dc.publisher | Ovid Technologies (Wolters Kluwer Health) | |
| dc.relation.ispartof | Circulation | |
| dc.relation.isversionof | 10.1161/CIRCULATIONAHA.110.006437 | |
| dc.subject | Cell Membrane | |
| dc.subject | Intercellular Junctions | |
| dc.subject | Animals | |
| dc.subject | Mice, Transgenic | |
| dc.subject | Mice, Knockout | |
| dc.subject | Mice | |
| dc.subject | Calcium Channels | |
| dc.subject | Ryanodine Receptor Calcium Release Channel | |
| dc.subject | Membrane Proteins | |
| dc.subject | RNA, Small Interfering | |
| dc.subject | Myocardial Contraction | |
| dc.subject | Heart Failure | |
| dc.subject | Gene Knockdown Techniques | |
| dc.title | Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice. | |
| dc.type | Journal article | |
| duke.contributor.orcid | Landstrom, AP|0000-0002-1878-9631 | |
| pubs.begin-page | 979 | |
| pubs.end-page | 988 | |
| pubs.issue | 9 | |
| pubs.organisational-group | School of Medicine | |
| pubs.organisational-group | Cell Biology | |
| pubs.organisational-group | Pediatrics, Cardiology | |
| pubs.organisational-group | Duke | |
| pubs.organisational-group | Basic Science Departments | |
| pubs.organisational-group | Pediatrics | |
| pubs.organisational-group | Clinical Science Departments | |
| pubs.publication-status | Published | |
| pubs.volume | 123 |
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