{ "abstract": "Intracellular calcium waves in cardiac myocytes propagate through a fire-diffuse-fire mechanism in which calcium released from one RyR2 cluster diffuses to neighboring clusters and triggers their activation. Yet propagation faces a fundamental physical difficulty: the calcium signal must cross distances of 1–2 μm between Z-planes while being attenuated by cytosolic buffering and diffusion, and at the same time the release site depletes its local sarcoplasmic reticulum calcium store. How waves propagate efficiently despite these constraints has remained unclear. We developed a three-dimensional computational model of mouse ventricular myocytes at submicrometer resolution to address this question. Our central finding is that co-localization of calsequestrin2 (CASQ2) with RyR2 clusters is required for robust wave propagation. In a physiological model, where CASQ2 is concentrated at release sites as observed experimentally, calcium waves propagate reliably across the cell with velocities that match the experimental range. In contrast, when CASQ2 is distributed uniformly throughout the sarcoplasmic reticulum, keeping total CASQ2 unchanged, the wavefront stalls. These results identify CASQ2–RyR2 co-localization as a key structural requirement for effective calcium wave propagation in ventricular myocytes. Author summary: Calcium waves in cardiomyocytes are thought to underlie the onset of malignant cardiac arrhythmias, such as ventricular tachycardia and fibrillation. Yet, the specific conditions that regulate the transition from local calcium sparks to sustained waves remain poorly understood. Using a newly developed computational model of calcium handling, we demonstrate that the spatial distribution of key regulatory proteins is a critical determinant of arrhythmogenicity. Specifically, we found that CASQ2, which buffers Ca2+ within the sarcoplasmic reticulum, must be strictly colocalized with Ca2+ release proteins to facilitate sustained wave propagation. This discovery suggests that cardiac stability depends less on the total quantity of protein and more on its precise architectural organization. The consequences of this finding are significant: it implies that “spatial dysregulation”–-where proteins are present but mislocalized–-may be a hidden driver of arrhythmias even when protein levels appear normal. This shifts the therapeutic focus from simply altering ion channel conductance to preserving or restoring the structural tethering of the junctional SR. By focusing on the nanodomain architecture, we can better understand how cellular remodeling leads to life-threatening electrical instability.", "abstract_shown": true, "affiliations": [ "Department of Physics and Institute for Research and Innovation in Health (IRIS), Universitat Politècnica de Catalunya - BarcelonaTech, Barcelona, Spain", "Institut de Recerca de Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain", "Instituto de Investigaciones Biomédicas de Barcelona (IIBB-CSIC), Barcelona, Spain", "CIBER de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain", "Department of Physics and Astronomy, California State University Northridge, Northridge, California, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 5, "authors": [ { "affs": [ 0 ], "name": "David Conesa" }, { "affs": [ 1 ], "name": "Blas Echebarria" }, { "affs": [ 2 ], "name": "Leif Hove-Madsen" }, { "affs": [ 3 ], "name": "Yohannes Shiferaw" }, { "affs": [ 4 ], "name": "Enrique Alvarez-Lacalle" } ], "bibtex": "https://research.draconitic.com/paper/dxt0z0gdpx8n9.bib", "cited_by": 0, "doi": "10.1371/journal.pcbi.1014449", "fulltext_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014449", "id": "dxt0z0gdpx8n9", "issns": [ "1553-7358" ], "landing_url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014449", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2705|Cardiac electrophysiology and arrhythmias" ], [ "plos", "/Biology and life sciences/Anatomy/Biological tissue/Muscle tissue/Muscle cells" ], [ "plos", "/Biology and life sciences/Biochemistry/Proteins/Ion channels/Calcium channels" ], [ "plos", "/Biology and life sciences/Biophysics/Ion channels/Calcium channels" ], [ "plos", "/Biology and life sciences/Cell biology/Cell physiology" ], [ "plos", "/Biology and life sciences/Cell biology/Cell processes/Cellular extrusion" ], [ "plos", "/Biology and life sciences/Cell biology/Cell processes/Secretory pathway/Endoplasmic reticulum/Sarcoplasmic reticula" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular structures and organelles/Endoplasmic reticulum/Sarcoplasmic reticula" ], [ "plos", "/Biology and life sciences/Cell biology/Cellular types/Animal cells/Muscle cells" ], [ "plos", "/Biology and life sciences/Cell biology/Signal transduction/Cell signaling/Calcium signaling" ], [ "plos", "/Biology and life sciences/Evolutionary biology/Evolutionary physiology" ], [ "plos", "/Biology and life sciences/Neuroscience/Neurophysiology/Ion channels/Calcium channels" ], [ "plos", "/Biology and life sciences/Physiology/Electrophysiology/Ion channels/Calcium channels" ], [ "plos", "/Biology and life sciences/Physiology/Electrophysiology/Neurophysiology/Ion channels/Calcium channels" ], [ "plos", "/Medicine and health sciences/Anatomy/Biological tissue/Muscle tissue/Muscle cells" ], [ "plos", "/Physical sciences/Physics/Biophysics/Ion channels/Calcium channels" ], [ "plos", "/Physical sciences/Physics/Waves/Wave propagation" ] ], "openalex": "W7223686091", "pdf_url": "https://journals.plos.org/ploscompbiol/article/file?id=10.1371/journal.pcbi.1014449&type=printable", "pmcid": null, "pmid": null, "published": "2026-10-26", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/dxt0z0gdpx8n9.ris", "sources": [ { "first_seen": "2026-10-30T12:17:17Z", "native_id": "10.1371/journal.pcbi.1014449", "source": "plos", "url": "https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014449" } ], "subjects": [ { "field": "biology", "origin": "plos:cell biology", "subfield": "cell-biology" }, { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "Calsequestrin localization at RyR2 clusters enables calcium wave propagation in ventricular myocytes", "title_text": "Calsequestrin localization at RyR2 clusters enables calcium wave propagation in ventricular myocytes", "type": "peer-reviewed", "updated_at": "2026-10-30T12:17:17Z", "url": "https://research.draconitic.com/paper/dxt0z0gdpx8n9", "venue": "PLOS Computational Biology", "versions": [] }