A duo of redox-sensitive pore-loop cysteines controls the activity of the neural ion channel TRPM3

A duo of redox-sensitive pore-loop cysteines controls the activity of the neural ion channel TRPM3 | 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 A duo of redox-sensitive pore-loop cysteines controls the activity of the neural ion channel TRPM3 Katharina Held, Evelien Van Hoeymissen, Ilhem Dallali, Eleonora Persoons, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3911792/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Jan, 2026 Read the published version in Communications Chemistry → Version 1 posted You are reading this latest preprint version Abstract Transient Receptor Potential Melastatin 3 (TRPM3) is a non-selective, Ca 2+ -permeable ion channel that plays a pivotal role in peripheral thermosensation and nociception. Moreover, gain-of-function variants in TRPM3 underlie a spectrum of neurodevelopmental and epileptic disorders in humans, indicating an important role of TRPM3 in the central nervous system. Oxidative stress contributes to various neurological disorders of both the central and peripheral nervous system, but it is unknown whether TRPM3 activity is altered by the cellular redox state. Here, we report a direct, bidirectional modification of TRPM3 channel activity by oxidizing and reducing agents. Our data, obtained both in a heterologous expression system and in mouse sensory neurons and pancreatic islet cells, demonstrate a profound effect of the redox state on the channel properties of TRPM3, including a robust shift in the response profile to TRPM3 agonists and antagonists and in the modulation by G protein-coupled receptors. In addition, we identified two cysteine residues in the extracellular pore loop of TRPM3 that underlie the redox-control of the channel, due to the reversible formation of intra-subunit cysteine bridges. Taken together, these findings establish a novel mechanism of TRPM3 channel modulation, with potentially important ramifications for pain signaling and neurological disorders. Biological sciences/Physiology/Neurophysiology Biological sciences/Neuroscience/Ion channels in the nervous system Health sciences/Neurology/Neurological disorders Full Text Additional Declarations Yes there is potential Competing Interest. J.V. and T.V. are co-inventors on patents entitled “treatment of pain” derived from 412 WO2012149614. All other authors declare no conflict of interest. Supplementary Files SupplementaryFiguresHeldetal.2024.pdf Cite Share Download PDF Status: Published Journal Publication published 14 Jan, 2026 Read the published version in Communications Chemistry → 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-3911792","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":272520267,"identity":"b23f2940-4408-4abc-8af6-7d6fe256e2a4","order_by":0,"name":"Katharina 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All other authors declare no conflict of interest.","formattedTitle":"A duo of redox-sensitive pore-loop cysteines controls the activity of the neural ion channel TRPM3","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":true,"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-3911792/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3911792/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Transient Receptor Potential Melastatin 3 (TRPM3) is a non-selective, Ca\u003csup\u003e2+\u003c/sup\u003e-permeable ion channel that plays a pivotal role in peripheral thermosensation and nociception. Moreover, gain-of-function variants in TRPM3 underlie a spectrum of neurodevelopmental and epileptic disorders in humans, indicating an important role of TRPM3 in the central nervous system. Oxidative stress contributes to various neurological disorders of both the central and peripheral nervous system, but it is unknown whether TRPM3 activity is altered by the cellular redox state. Here, we report a direct, bidirectional modification of TRPM3 channel activity by oxidizing and reducing agents. Our data, obtained both in a heterologous expression system and in mouse sensory neurons and pancreatic islet cells, demonstrate a profound effect of the redox state on the channel properties of TRPM3, including a robust shift in the response profile to TRPM3 agonists and antagonists and in the modulation by G protein-coupled receptors. In addition, we identified two cysteine residues in the extracellular pore loop of TRPM3 that underlie the redox-control of the channel, due to the reversible formation of intra-subunit cysteine bridges. 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