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

Ralph J. Van Oort, Alejandro Garbino, Wei Wang, Sayali S. Dixit, Andrew P. Landstrom, Namit Gaur, Angela C. De Almeida, Darlene G. Skapura, Yoram Rudy, Alan R. Burns, Michael J. Ackerman, Xander H.T. Wehrens

Research output: Contribution to journalArticle

151 Scopus citations

Abstract

Background- 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 Ca2+-induced Ca 2+ release process in the heart. Our recent work demonstrated loss-of-function mutations in JPH2 in patients with hypertrophic cardiomyopathy. Methods and Results- 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. Conclusions- 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.

Original languageEnglish (US)
Pages (from-to)979-988
Number of pages10
JournalCirculation
Volume123
Issue number9
DOIs
StatePublished - Mar 8 2011

Keywords

  • calcium
  • excitation
  • heart failure
  • junctophilin
  • sarcoplasmic reticulum

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Van Oort, R. J., Garbino, A., Wang, W., Dixit, S. S., Landstrom, A. P., Gaur, N., De Almeida, A. C., Skapura, D. G., Rudy, Y., Burns, A. R., Ackerman, M. J., & Wehrens, X. H. T. (2011). Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice. Circulation, 123(9), 979-988. https://doi.org/10.1161/CIRCULATIONAHA.110.006437