ArticleJournal of the American Heart Association2014
Calpain-dependent cleavage of junctophilin-2 and T-tubule remodeling in a mouse model of reversible heart failure.
Article in Journal of the American Heart Association, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 61 citations in OpenAlex.
- Cardiac unloading models for myocardial reverse remodeling.Basic research in cardiology · 2026Review
- Active Colitis Attenuates Ventricular Excitation-Contraction Coupling by T-Tubular Remodeling.Biomolecules · 2026Article
- Increased Intermembrane Space [CaCirculation research · 2025Article
- Metabolic-Electrophysiological Coupling in Heart Failure: from Bidirectional Decoupling to Therapeutic Recoupling.Current heart failure reports · 2025Review
- Nonstructural Roles of Junctophilin-2 in the Heart.JACC. Basic to translational science · 2025Review
- Preventing Site-Specific Calpain Proteolysis of Junctophilin-2 Protects Against Stress-Induced Excitation-Contraction Uncoupling and Heart Failure Development.Circulation · 2025Article
- Efficacy of a cysteine protease inhibitor compared with enalapril in murine heart failure models.iScience · 2024Article
- Targeting calpain-2-mediated junctophilin-2 cleavage delays heart failure progression following myocardial infarction.Journal of molecular and cellular cardiology · 2024Article
- Structure, Function, and Regulation of the Junctophilin Family.Annual review of physiology · 2024Review
- Article
- Speg interactions that regulate the stability of excitation-contraction coupling protein complexes in triads and dyads.Communications biology · 2023Article
- Article
- NMR resonance assignments of the DNA binding domain of mouse Junctophilin-2.Biomolecular NMR assignments · 2022Article
- The role of junctophilin proteins in cellular function.Physiological reviews · 2022Review
- Calpain cleavage of Junctophilin-2 generates a spectrum of calcium-dependent cleavage products and DNA-rich NTScientific reports · 2022Article
- Gene Therapy With the N-Terminus of Junctophilin-2 Improves Heart Failure in Mice.Circulation research · 2022Article
- Structures of the junctophilin/voltage-gated calcium channel interface reveal hot spot for cardiomyopathy mutations.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- The Builders of the Junction: Roles of Junctophilin1 and Junctophilin2 in the Assembly of the Sarcoplasmic Reticulum-Plasma Membrane Junctions in Striated Muscle.Biomolecules · 2022Review
- Calpain-2 specifically cleaves Junctophilin-2 at the same site as Calpain-1 but with less efficacy.The Biochemical journal · 2021Article
- Targeted inhibition of calpain in mitochondria alleviates oxidative stress-induced myocardial injury.Acta pharmacologica Sinica · 2021Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundA highly organized transverse tubule (T-tubule) network is necessary for efficient Ca(2+)-induced Ca(2+) release and synchronized contraction of ventricular myocytes. Increasing evidence suggests that T-tubule remodeling due to junctophilin-2 (JP-2) downregulation plays a critical role in the progression of heart failure. However, the mechanisms underlying JP-2 dysregulation remain incompletely understood. METHODS AND
resultsA mouse model of reversible heart failure that is driven by conditional activation of the heterotrimeric G protein Gαq in cardiac myocytes was used in this study. Mice with activated Gαq exhibited disruption of the T-tubule network and defects in Ca(2+) handling that culminated in heart failure compared with wild-type mice. Activation of Gαq/phospholipase Cβ signaling increased the activity of the Ca(2+)-dependent protease calpain, leading to the proteolytic cleavage of JP-2. A novel calpain cleavage fragment of JP-2 is detected only in hearts with constitutive Gαq signaling to phospholipase Cβ. Termination of the Gαq signal was followed by normalization of the JP-2 protein level, repair of the T-tubule network, improvements in Ca(2+) handling, and reversal of heart failure. Treatment of mice with a calpain inhibitor prevented Gαq-dependent JP-2 cleavage, T-tubule disruption, and the development of heart failure.
conclusionsDisruption of the T-tubule network in heart failure is a reversible process. Gαq-dependent activation of calpain and subsequent proteolysis of JP-2 appear to be the molecular mechanism that leads to T-tubule remodeling, Ca(2+) handling dysfunction, and progression to heart failure in this mouse model.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.