Autonomous circadian oscillators intrinsic to cell membranes

Autonomous circadian oscillators intrinsic to cell membranes | 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 Biological Sciences - Article Autonomous circadian oscillators intrinsic to cell membranes Mauro Forlino, Oreste Piro, Monika Stengl, Martin Garcia This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8788655/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 Circadian rhythms, originating in endogenous cellular clockworks, are the evolutionary solution that allows organisms to anticipate and synchronize their internal processes with the predictable changes in their environment on a daily basis. Across evolution, circadian oscillators share a conserved design based on delayed negative feedbacks, yet differ in their molecular implementation in prokaryotes and eukaryotes. Although eukaryotic circadian timing is conventionally assumed to originate from nuclear transcription-translation feedback loop (TTFL) clockworks, mounting evidence indicates that daily rhythms can also persist in cells devoid of such nuclear clocks, including the circadian variation of metabolism and redox state in red blood cells. Here, we demonstrate the generation of endogenous circadian oscillations through a membrane-associated post-translational feedback loop (PTFL) mechanism that operates independently of the nuclear TTFL clock and relies on the dynamic regulation of ion channel gating. This mechanism accounts for the circadian oscillations observed in potassium transport, redox state, and metabolism in anucleate red blood cells. The same membrane-associated mechanism may operate in nucleated cells as well. In circadian clock neurons, it could clarify rhythmic changes in ion channel conductances that cannot be attributed to the nuclear TTFL oscillator. Oscillations in ion fluxes directly modulate neuronal excitability, potentially giving rise to spontaneous circadian firing rhythms and synchronized bursting. Biological sciences/Computational biology and bioinformatics/Computational models Physical sciences/Physics/Statistical physics, thermodynamics and nonlinear dynamics/Nonlinear phenomena Full Text Additional Declarations There is NO Competing Interest. 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. 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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-8788655","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":586491583,"identity":"17dcbec0-8705-474c-bf87-80bbbea088b8","order_by":0,"name":"Mauro Forlino","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIie3PsUrDQBzH8d8RuCwXXSMp8QmEk4M4VHwWQ6AuQYcuHRwChcsrpCD6EELnwEGngGvdOsXFId0iBPROBB2u1tHhvhmOQD75/w9wuf5vMeCTApgBVD+mEXD5GxGAZ0jzTdgfiD6INC97yEnZJF0HHp/NPbnZ3qvrA9B02w/nDH5W20jS5GJRgYuRIuXpYqmmejEVBXLCwFrrmKTOhccwpJVHZBQsVSqPX4qIFIohzLmVPL0awr/InSbw52/98K7JTWcl6/wnKQyhq5DR2kyxXj9Zt1NScS5CTY6q1ZUhk3EgM0ZZu2Ox7BHdjMehX7ZhdztOHwoqnvvhIj70s411zGfWv9Hd37tcLpdrTx+NF1Lz4Qx8awAAAABJRU5ErkJggg==","orcid":"","institution":"University of Kassel","correspondingAuthor":true,"prefix":"","firstName":"Mauro","middleName":"","lastName":"Forlino","suffix":""},{"id":586491584,"identity":"f40b1b28-3af2-4485-a282-6a440f0dd5c0","order_by":1,"name":"Oreste Piro","email":"","orcid":"","institution":"University of the Balearic Islands","correspondingAuthor":false,"prefix":"","firstName":"Oreste","middleName":"","lastName":"Piro","suffix":""},{"id":586491585,"identity":"c99d9f68-bcee-43dd-baa9-053f4df0b9fd","order_by":2,"name":"Monika Stengl","email":"","orcid":"","institution":"University of Kassel","correspondingAuthor":false,"prefix":"","firstName":"Monika","middleName":"","lastName":"Stengl","suffix":""},{"id":586491586,"identity":"2c7fe39d-fe25-44c4-b3ad-3f8d6a23bda2","order_by":3,"name":"Martin Garcia","email":"","orcid":"https://orcid.org/0000-0003-2418-1902","institution":"University of Kassel","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"","lastName":"Garcia","suffix":""}],"badges":[],"createdAt":"2026-02-04 16:13:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8788655/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8788655/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102764501,"identity":"59415bee-4ba3-4a87-a9a0-50142d0182a4","added_by":"auto","created_at":"2026-02-16 11:12:27","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":704605,"visible":true,"origin":"","legend":"Article File","description":"","filename":"Autonomouscircadianoscillatorsintrinsictocellmembranes.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8788655/v1_covered_707e1d95-5a44-4a1d-bb55-0bf1247ac45e.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Autonomous circadian oscillators intrinsic to cell membranes","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 Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8788655/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8788655/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Circadian rhythms, originating in endogenous cellular clockworks, are the evolutionary solution that allows organisms to anticipate and synchronize their internal processes with the predictable changes in their environment on a daily basis. \r\nAcross evolution, circadian oscillators share a conserved design based on delayed negative feedbacks, yet differ in their molecular implementation in prokaryotes and eukaryotes. 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