Modelling CK2-dependent phosphorylation and ankyrin-G binding in sodium channel recruitment to the axon initial segment

Modelling CK2-dependent phosphorylation and ankyrin-G binding in sodium channel recruitment to the axon initial segment | 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 Research Article Modelling CK2-dependent phosphorylation and ankyrin-G binding in sodium channel recruitment to the axon initial segment Don Kulasiri This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9558857/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 The axon initial segment (AIS) is essential for action potential initiation due to the high density of voltage-gated sodium (Nav) channels localized in this region. The recruitment of Nav channels to the AIS is mediated by ankyrin-G (AnkG) and regulated by phosphorylation via casein kinase 2 (CK2), yet the dynamic interplay between these processes remains poorly understood. In this study, we develop a mathematical model to investigate the coupled roles of CK2-mediated phosphorylation and AnkG binding in Nav channel recruitment. The model incorporates distinct molecular states of Nav channels and describes their transitions through a system of coupled kinetic equations. Our results show that phosphorylation acts as a regulatory mechanism controlling the availability of AnkG-binding-competent Nav states. The model further reveals nonlinear behaviour in channel recruitment, with phosphorylation kinetics leading to significant variations in Nav localization. Analysis identifies key parameters governing system dynamics, suggesting potential mechanisms by which disruptions in CK2 or AnkG function may contribute to neuronal dysfunction. These findings provide a quantitative framework for understanding AIS assembly and generate testable predictions for experimental studies of Nav channel localization and associated neurological disorders. Axon initial segment (AIS) model Sodium channels Ankyrin-G micro-states macro-states mathematical modelling phosphorylation CK2 Full Text Additional Declarations No competing interests reported. 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. 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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-9558857","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":637643304,"identity":"c7eeb162-9864-4857-abbf-4f63f81c263d","order_by":0,"name":"Don Kulasiri","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABBUlEQVRIie3QsWoCMRjA8S8c2OVa18+lvsLn1BPUvorHrSKFQukgckXILde6npOvcH2DC4HrEuzq2HuDm0on8TvBThEdHfKfQpJfSALgcl1jBYCIIQDweFw/IU958SUED0Rl1BBxKWmO9wnOk7uv90KsJHa7yW2lBxRM28mb/IHZCB7ahZV0zGYsPiX2cn1DekL4jEYlBGUE/dhOaDshUUkUudeChoQ5hhKhVQAp+wWP5HG9YBL8kx0TbX/LgfDFwlgzgSMRkklpJx1jSGUbjHImKmWSGcUnfEQ+mVM/lvaq9GUwXC9Lr/57nYfLZFFi/Tu6p2/785ssK2MA/+R+l8vlcp1tD/A6XVQi3T06AAAAAElFTkSuQmCC","orcid":"","institution":"Lincoln University","correspondingAuthor":true,"prefix":"","firstName":"Don","middleName":"","lastName":"Kulasiri","suffix":""}],"badges":[],"createdAt":"2026-04-29 00:38:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9558857/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9558857/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":108935017,"identity":"21b84d84-12cb-46cb-9a5d-815b9e3d412c","added_by":"auto","created_at":"2026-05-11 03:26:15","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":798474,"visible":true,"origin":"","legend":"","description":"","filename":"ManuscriptDK29April2026.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9558857/v1_covered_dfac6849-c82e-4bef-a1dd-7851467975d6.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Modelling CK2-dependent phosphorylation and ankyrin-G binding in sodium channel recruitment to the axon initial segment","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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 Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Axon initial segment (AIS), model, Sodium channels, Ankyrin-G, micro-states, macro-states, mathematical modelling, phosphorylation, CK2","lastPublishedDoi":"10.21203/rs.3.rs-9558857/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9558857/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe axon initial segment (AIS) is essential for action potential initiation due to the high density of voltage-gated sodium (Nav) channels localized in this region. The recruitment of Nav channels to the AIS is mediated by ankyrin-G (AnkG) and regulated by phosphorylation via casein kinase 2 (CK2), yet the dynamic interplay between these processes remains poorly understood.\u003c/p\u003e \u003cp\u003eIn this study, we develop a mathematical model to investigate the coupled roles of CK2-mediated phosphorylation and AnkG binding in Nav channel recruitment. The model incorporates distinct molecular states of Nav channels and describes their transitions through a system of coupled kinetic equations.\u003c/p\u003e \u003cp\u003eOur results show that phosphorylation acts as a regulatory mechanism controlling the availability of AnkG-binding-competent Nav states. The model further reveals nonlinear behaviour in channel recruitment, with phosphorylation kinetics leading to significant variations in Nav localization. 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