ArticleHeart rhythm2016
JPH-2 interacts with Cai-handling proteins and ion channels in dyads: Contribution to premature ventricular contraction-induced cardiomyopathy.
Article in Heart rhythm, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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39 citing papers in PubMed, 1 synthesis or guideline pooled it, 58 citations in OpenAlex.
- One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2.Trends in cardiovascular medicine · 2023Pooled it
- Outcomes of Premature Ventricular Contraction-Cardiomyopathy in the Veteran Population: A Secondary Analysis of the CHF-STAT Study.JACC. Clinical electrophysiology · 2021Trial
- Nonstructural Roles of Junctophilin-2 in the Heart.JACC. Basic to translational science · 2025Review
- Environment-induced heat stress causes ventricular-dependent biochemical changes in the heart in female pigs.Physiological reports · 2025Article
- Functional analysis of JPH2-knockout cardiomyocytes identifies ECCD as a novel indicator in a human cardiac modelJPH2.Stem cell research & therapy · 2025Article
- Prevalence of frequent premature ventricular contractions and left-ventricular systolic dysfunction in patients receiving Holter monitoring.Journal of cardiovascular electrophysiology · 2025Article
- Structure, Function, and Regulation of the Junctophilin Family.Annual review of physiology · 2024Review
- Mechanisms and Risk Factors for Premature Ventricular Contraction Induced Cardiomyopathy.Reviews in cardiovascular medicine · 2023Review
- Mechanisms of adaptive hypertrophic cardiac remodeling in a large animal model of premature ventricular contraction-induced cardiomyopathy.IUBMB life · 2023Article
- Impact of Premature Ventricular Complex (PVC) Burden on the Left Ventricle in the Structurally Normal Heart: Hemodynamic Alterations of Idiopathic PVC on Echocardiography.Acta Cardiologica Sinica · 2023Article
- Alterations of sarcoplasmic reticulum-mediated CaMolecular and cellular biochemistry · 2023Article
- Article
- Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling.The Journal of general physiology · 2022Review
- The role of junctophilin proteins in cellular function.Physiological reviews · 2022Review
- Electrical management of heart failure: from pathophysiology to treatment.European heart journal · 2022Review
- A bridge from the endoplasmic reticulum to the plasma membrane comes into view.Proceedings of the National Academy of Sciences of the United States of America · 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
- Understanding the molecular basis of cardiomyopathy.American journal of physiology. Heart and circulatory physiology · 2022Review
- 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
- Left ventricular dyssynchrony as marker of early dysfunction in premature ventricular contraction-induced cardiomyopathy.Frontiers in cardiovascular medicine · 2022Article
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8 authors at 3 institutions in 1 country.
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Abstract
backgroundIn a canine model of premature ventricular contraction-induced cardiomyopathy (PVC-CM), Cav1.2 is downregulated and misplaced from transverse tubules (T tubules). Junctophilin-2 (JPH-2) is also downregulated.
objectivesThe objectives of this study were to understand the role of JPH-2 in PVC-CM and to probe changes in other proteins involved in dyad structure and function.
methodsWe quantify T-tubule contents (di-8-ANEPPS fluorescence in live myocytes), examine myocyte ultrastructures (electron microscopy), probe JPH-2-interacting proteins (co-immunoprecipitation), quantify dyad and nondyad protein levels (immunoblotting), and examine subcellular distributions of dyad proteins (immunofluorescence/confocal microscopy). We also test direct JPH-2 modulation of channel function (vs indirect modulation through dyad formation) using heterologous expression.
resultsPVC myocytes have reduced T-tubule contents but otherwise normal ultrastructures. Among 19 proteins examined, only JPH-2, bridging integrator-1 (BIN-1), and Cav1.2 are highly downregulated in PVC hearts. However, statistical analysis indicates a general reduction in dyad protein levels when JPH-2 is downregulated. Furthermore, several dyad proteins, including Na/Ca exchanger, are missing or shifted from dyads to the peripheral surface in PVC myocytes. JPH-2 directly or indirectly interacts with Cai-handling proteins, Cav1.2 and KCNQ1, although not BIN-1 or other scaffolding proteins tested. Expression in mammalian cells that do not have dyads confirms direct JPH-2 modulation of the L-type Ca channel current (Cav1.2/voltage-gated Ca channel β subunit 2) and slow delayed rectifier current (KCNQ1/KCNE1).
conclusionJPH-2 is more than a "dyad glue": it can modulate Cai handling and ion channel function in the dyad region. Downregulation of JPH-2, BIN-1, and Cav1.2 plays a deterministic role in PVC-CM. Dissecting the hierarchical relationship among the three is necessary for the design of therapeutic interventions to prevent the progression of PVC-CM.
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