ArticleThe Journal of physiology2021
Increasing SERCA function promotes initiation of calcium sparks and breakup of calcium waves.
Article in The Journal of physiology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 31 citations in OpenAlex.
- Increased CaCells · 2026Article
- Abnormal calcium release and delayed afterdepolarizations: A comparison of two mathematical models for human ventricular myocytes.PloS one · 2026Article
- Intracellular CaBiologia futura · 2025Review
- Role of Dyadic Proteins in Proper Heart Function and Disease.International journal of molecular sciences · 2025Review
- SERCA2a dysfunction in the pathophysiology of heart failure with preserved ejection fraction: a direct role is yet to be established.Heart failure reviews · 2025Review
- Role of ryanodine receptor cooperativity in CaThe Journal of physiology · 2024Article
- Interpreting Diastolic Dynamics and Evaluation through Echocardiography.Life (Basel, Switzerland) · 2024Review
- Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation.JACC. Basic to translational science · 2024Review
- Fluorescence lifetime FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators.Scientific reports · 2023Article
- FRET assay for live-cell high-throughput screening of the cardiac SERCA pump yields multiple classes of small-molecule allosteric modulators.Research square · 2023Article
- Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction coupling and modulates arrhythmogenic dynamics.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2022Article
- Biological noise is a key determinant of the reproducibility and adaptability of cardiac pacemaking and EC coupling.The Journal of general physiology · 2022Review
- Exercise Causes Arrhythmogenic Remodeling of Intracellular Calcium Dynamics in Plakophilin-2-Deficient Hearts.Circulation · 2022Article
- Article
- Multi-Scale Computational Modeling of Spatial Calcium Handling From Nanodomain to Whole-Heart: Overview and Perspectives.Frontiers in physiology · 2022Review
- Fine-tuning SERCA activity to treat distinct heart failure syndromes.The Journal of physiology · 2021Article
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3 authors at 2 institutions in 2 countries.
Funding
Abstract
key pointsIncreasing sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) pump activity enhances sarcoplasmic reticulum calcium (Ca) load, which increases both ryanodine receptor opening and driving force of Ca release flux. Both of these effects promote Ca spark formation and wave propagation. However, increasing SERCA activity also accelerates local cytosolic Ca decay as the wave front travels to the next cluster, which limits wave propagation. As a result, increasing SERCA pump activity has a biphasic effect on the propensity of arrhythmogenic Ca waves, but a monotonic effect to increase Ca spark frequency and amplitude. ABSTRACT: Waves of sarcoplasmic reticulum (SR) calcium (Ca) release can cause arrhythmogenic afterdepolarizations in cardiac myocytes. Ca waves propagate when Ca sparks at one Ca release unit (CRU) recruit new Ca sparks in neighbouring CRUs. Under normal conditions, Ca sparks are too small to recruit neighbouring Ca sparks where Ca sensitivity is also low. However, under pathological conditions such as a Ca overload or ryanodine receptor (RyR) sensitization, Ca sparks can be larger and propagate more readily as macro-sparks or full Ca waves. Increasing SERCA pump activity promotes SR Ca load, which promotes RyR opening and increases driving force of the Ca release flux from SR to cytosol, promoting Ca waves. However, high sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) activity can also decrease local cytosolic [Ca] as it approaches the next CRU, thereby reducing wave appearance and propagation. In this study, we use a physiologically detailed model of subcellular Ca cycling and experiments in phospholamban-knockout mice, to show how Ca waves are initiated and propagate and how different conditions contribute to the generation and propagation of Ca waves. We show that reducing diffusive coupling between Ca sparks by increasing SERCA activity prevents Ca waves by reducing [Ca] at the next CRU, as do Ca buffers, low intra-SR Ca diffusion and distance between CRUs. Increasing SR Ca uptake rate has a biphasic effect on Ca wave propagation; initially it enhances Ca spark probability and amplitude and CRU coupling, thereby promoting arrhythmogenic Ca wave propagation, but at higher levels SR Ca uptake can abort those arrhythmogenic Ca waves.
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