期刊
CIRCULATION
卷 123, 期 9, 页码 979-U123出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.110.006437
关键词
calcium; excitation; heart failure; junctophilin; sarcoplasmic reticulum
资金
- American Physiological Society
- American Heart Association
- National Institutes of Health/National Heart, Lung, and Blood Institute [R01-HL033343, R01-HL049054, R01-HL089598, R01-HL091947]
- National Science Foundation [CBET-0929633]
- National Institutes of Health/National Eye Institute [R01-EY017120, P30-EY007551]
- National Institutes of Health [R01-HD42569, P01-HL94291]
- Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program
- Muscular Dystrophy Association [69238]
- Fondation Leducq Award
- Div Of Chem, Bioeng, Env, & Transp Sys
- Directorate For Engineering [0929633] Funding Source: National Science Foundation
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 Ca2+ 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. (Circulation. 2011; 123: 979-988.)
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