Lysosomal signalling pathways influence heart rhythm, and regulate atrial function

Lysosomal signalling pathways influence heart rhythm, and regulate atrial function | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Lysosomal signalling pathways influence heart rhythm, and regulate atrial function REBECCA Burton, Rebecca Capel, Emily Akerman, Eva Rog-Zielinska, and 35 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4557026/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract In the heart, endogenous nicotinic acid adenine dinucleotide phosphate (NAADP) triggers lysosomal calcium release to augment sarcoplasmic reticulum (SR) calcium sequestration, producing larger calcium transients. However, the role of lysosomal calcium signals in pacemaker activity, a distinct calcium-operated function of the sino-atrial node (SAN) or atria, a distinct calcium-operated function, has not been investigated. Pharmacological or genetic ablation of the NAADP pathway inhibits spontaneous beating rate response to β-adrenergic stimulation in intact SAN. We found intracellular signalling microdomains between lysosomes and neighbouring SR or mitochondria in mouse, rabbit, goat, and human atrial tissue. The spatial relationship between lysosomes and other calcium-handling organelles are altered in goat and human atrial fibrillation. Furthermore, we demonstrate atrial myocytes produce 3′–5′-cyclic adenosine monophosphate in response to lysosomal signalling, adding a novel trigger for cyclic nucleotide signalling. Our findings support the hypothesis that lysosomal calcium signaling directly increases cardiomyocyte cAMP and modulates pacemaker activity. Biological sciences/Physiology Biological sciences/Cell biology/Cell signalling Full Text Additional Declarations There is NO Competing Interest. Supplementary Files SupplementaryFile1EXCELvolcanoplotAFSR.xlsx Dataset 1 SupplementaryFile2HumanDIAPASEFAFvSR2024.xlsx Dataset 2 SupplementaryFile3RelatedtoFigure9Pathways.xls Dataset 3 SupplementalVideoFile1mouse1SAN.avi Mouse Sino-Atrial Node tissue in 3D tomogram video SupplementalVideoFile2goatcontrol.avi Left atrial goat tissue (sham control) in 3D tomogram video SupplementalVideoFile3goatAF1.avi Left atrial AF goat tissue (atrial fibrillation) in 3D tomogram video SupplementalVideoFile4Humantomogram.mp4 A simple segmented video from human left atrial tomogram Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4557026","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":314589276,"identity":"57589a01-e39c-412e-b08e-597ee9f7b8aa","order_by":0,"name":"REBECCA 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Interest.","formattedTitle":"Lysosomal signalling pathways influence heart rhythm, and \r\nregulate atrial function","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research 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However, the role of lysosomal calcium signals in pacemaker activity, a distinct \r\ncalcium-operated function of the sino-atrial node (SAN) or atria, a distinct calcium-operated function, has not been investigated. Pharmacological or genetic ablation of the NAADP pathway inhibits spontaneous beating rate response to β-adrenergic stimulation in intact SAN. We found intracellular signalling microdomains between lysosomes and neighbouring SR or mitochondria in mouse, rabbit, goat, and human atrial tissue. The spatial relationship between lysosomes and other calcium-handling organelles are altered in goat and human atrial fibrillation. Furthermore, we demonstrate atrial myocytes produce 3′–5′-cyclic adenosine monophosphate in response to lysosomal signalling, adding a novel trigger for cyclic nucleotide signalling. 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