HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Ablation of triadin causes loss of cardiac Ca2+ release units, impaired excitation-contraction coupling, and cardiac arrhythmias.

Abstract
Heart muscle excitation-contraction (E-C) coupling is governed by Ca(2+) release units (CRUs) whereby Ca(2+) influx via L-type Ca(2+) channels (Cav1.2) triggers Ca(2+) release from juxtaposed Ca(2+) release channels (RyR2) located in junctional sarcoplasmic reticulum (jSR). Although studies suggest that the jSR protein triadin anchors cardiac calsequestrin (Casq2) to RyR2, its contribution to E-C coupling remains unclear. Here, we identify the role of triadin using mice with ablation of the Trdn gene (Trdn(-/-)). The structure and protein composition of the cardiac CRU is significantly altered in Trdn(-/-) hearts. jSR proteins (RyR2, Casq2, junctin, and junctophilin 1 and 2) are significantly reduced in Trdn(-/-) hearts, whereas Cav1.2 and SERCA2a remain unchanged. Electron microscopy shows fragmentation and an overall 50% reduction in the contacts between jSR and T-tubules. Immunolabeling experiments show reduced colocalization of Cav1.2 with RyR2 and substantial Casq2 labeling outside of the jSR in Trdn(-/-) myocytes. CRU function is impaired in Trdn(-/-) myocytes, with reduced SR Ca(2+) release and impaired negative feedback of SR Ca(2+) release on Cav1.2 Ca(2+) currents (I(Ca)). Uninhibited Ca(2+) influx via I(Ca) likely contributes to Ca(2+) overload and results in spontaneous SR Ca(2+) releases upon beta-adrenergic receptor stimulation with isoproterenol in Trdn(-/-) myocytes, and ventricular arrhythmias in Trdn(-/-) mice. We conclude that triadin is critically important for maintaining the structural and functional integrity of the cardiac CRU; triadin loss and the resulting alterations in CRU structure and protein composition impairs E-C coupling and renders hearts susceptible to ventricular arrhythmias.
AuthorsNagesh Chopra, Tao Yang, Parisa Asghari, Edwin D Moore, Sabine Huke, Brandy Akin, Robert A Cattolica, Claudio F Perez, Thinn Hlaing, Barbara E C Knollmann-Ritschel, Larry R Jones, Isaac N Pessah, Paul D Allen, Clara Franzini-Armstrong, Björn C Knollmann
JournalProceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 18 Pg. 7636-41 (May 05 2009) ISSN: 1091-6490 [Electronic] United States
PMID19383796 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • CACNA1C protein, mouse
  • Calcium Channels, L-Type
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • Trdn protein, mouse
  • Calcium
Topics
  • Animals
  • Arrhythmias, Cardiac (genetics, pathology, physiopathology)
  • Calcium (metabolism)
  • Calcium Channels, L-Type (metabolism)
  • Carrier Proteins (genetics, physiology)
  • Heart (physiology, physiopathology)
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Mutant Strains
  • Muscle Proteins (genetics, physiology)
  • Myocardial Contraction (genetics)
  • Myocardium (metabolism, ultrastructure)
  • Sarcoplasmic Reticulum (metabolism, ultrastructure)
  • Sequence Deletion

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: