Temperature-dependent gating pathways in TRPV3

Temperature-dependent gating pathways in TRPV3 | 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Download PDF Research Article Temperature-dependent gating pathways in TRPV3 Guangyu Wang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5759985/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 25 Mar, 2026 Read the published version in Scientific Reports → Version 2 posted You are reading this latest preprint version Show more versions Abstract Both hot and cold sensations of the homotetrameric thermosensitive transient receptor potential vanilloid 1–4 (TRPV1-4) channels have been predicted by a single Gibbs-Helmholtz equation for a change in molar heat capacity. However, the heat capacity model has not been examined for TRPV3 channels involving inactivation. Given the mirrored heat and cold sensitivity in TRPV1 with a shared starter, the same case should be detected for TRPV3. To test this hypothesis, the temperature-dependent quaternary and tertiary structures of oxidized TRPV3 in the presence and absence of the natural cannabinoid tetrahydrocannabivarin (THCV) at the active vanilloid site were characterized along a lipid-dependent gating pathway. Further thermoring analyses showed that gating state-dependent thermostability allowed oxidized TRPV3 to be activated and then inactivated by THCV only below 30°C. However, no inactivation would be observed above 30°C once the lipid at the active vanilloid site was released by THCV binding. More importantly, despite the distinct tertiary and quaternary structures in cold- and heat-evoked open states, the initial cold activation of oxidized TRPV3 still shared a similar thermosensitivity with heat activation. Therefore, such two temperature-dependent gating pathways of oxidized TRPV3 actually still resulted from symmetric cold and heat activation, supporting the heat capacity model, regardless of the subsequent inactivation. In contrast, the initial inactivation resulted in unpredictable pore dilation along with a tetramer-to-pentamer transition. (220 words) Biophysics Computational Biology Systems and Networking General Biochemistry Physiology ligand exchange heat capacity inactivation partial unfolding temperature sensitivity thermodynamic signature thermoring stability protein thermoactivity Full Text Additional Declarations The authors declare no competing interests. Supplementary Files SupportingInformationthermoswitchesinTRPV3R1.0.pdf Cite Share Download PDF Status: Published Journal Publication published 25 Mar, 2026 Read the published version in Scientific Reports → Version 2 posted You are reading this latest preprint version Show more versions 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. 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However, the heat capacity model has not been examined for TRPV3 channels involving inactivation. Given the mirrored heat and cold sensitivity in TRPV1 with a shared starter, the same case should be detected for TRPV3. To test this hypothesis, the temperature-dependent quaternary and tertiary structures of oxidized TRPV3 in the presence and absence of the natural cannabinoid tetrahydrocannabivarin (THCV) at the active vanilloid site were characterized along a lipid-dependent gating pathway. Further thermoring analyses showed that gating state-dependent thermostability allowed oxidized TRPV3 to be activated and then inactivated by THCV only below 30\u0026deg;C. However, no inactivation would be observed above 30\u0026deg;C once the lipid at the active vanilloid site was released by THCV binding. More importantly, despite the distinct tertiary and quaternary structures in cold- and heat-evoked open states, the initial cold activation of oxidized TRPV3 still shared a similar thermosensitivity with heat activation. Therefore, such two temperature-dependent gating pathways of oxidized TRPV3 actually still resulted from symmetric cold and heat activation, supporting the heat capacity model, regardless of the subsequent inactivation. In contrast, the initial inactivation resulted in unpredictable pore dilation along with a tetramer-to-pentamer transition. 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