{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T05:42:42Z","timestamp":1775886162759,"version":"3.50.1"},"posted":{"date-parts":[[2025,1,3]]},"group-title":"Neuroscience","reference-count":49,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,3]],"date-time":"2025-01-03T00:00:00Z","timestamp":1735862400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The Ca\n                  <jats:sub>V<\/jats:sub>\n                  3.2 isoform of T-type voltage-gated calcium channels plays a crucial role in regulating the excitability of nociceptive neurons; the endogenous molecules that modulate its activity, however, remain poorly understood. Here, we used serum proteomics and patch-clamp physiology to discover a novel peptide albumin (1-26) that facilitates channel gating by chelating trace metals that tonically inhibit Ca\n                  <jats:sub>V<\/jats:sub>\n                  3.2\n                  <jats:italic>via<\/jats:italic>\n                  H191 residue. Importantly, serum also potently modulated T-currents in human and rodent dorsal root ganglion (DRG) neurons.\n                  <jats:italic>In vivo<\/jats:italic>\n                  pain studies revealed that injections of serum and albumin (1-26) peptide resulted in robust mechanical and heat hypersensitivity. This hypersensitivity was abolished with a T-channel inhibitor, in Ca\n                  <jats:sub>V<\/jats:sub>\n                  3.2 null mice and in Ca\n                  <jats:sub>V<\/jats:sub>\n                  3.2 H191Q knock-in mice. The discovery of endogenous chelators of trace metals in the serum deepens our understanding of the role of Ca\n                  <jats:sub>V<\/jats:sub>\n                  3.2 channels in neuronal hyperexcitability and may facilitate the design of novel analgesics with unique mechanisms of action.\n                <\/jats:p>","DOI":"10.1101\/2025.01.03.631165","type":"posted-content","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T08:30:15Z","timestamp":1736238615000},"source":"Crossref","is-referenced-by-count":1,"title":["Facilitation of Ca\n                  <sub>V<\/sub>\n                  3.2 channel gating in pain pathways reveals a novel mechanism of serum-induced hyperalgesia"],"prefix":"10.64898","author":[{"given":"Karolina","family":"Sanner","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Kawell","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Grayson","family":"Evans","sequence":"additional","affiliation":[{"name":"Undergraduate College of Arts and Sciences and Graduate program in Neuroscience, University of Virginia, Charlottesville, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vida","family":"Elekovic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MacKenzie","family":"Walz","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonja Lj.","family":"Joksimovic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Srdjan M.","family":"Joksimovic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca R.","family":"Donald","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maja","family":"Tomic","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peihan","family":"Orestes","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Feseha","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annemarie","family":"Dedek","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Carleton University, Ottawa Hospital Research Institute ON"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seyed Mohammadreza","family":"Ghodsi","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabella P.","family":"Fallon","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeonghan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Busan Paik Hospital, Inje University, College of Medicine, Busan, South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung Mi","family":"Hwang","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Hallym University School of Medicine, Chuncheon Sacred Heart Hospital, South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung Jun","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine, Kangdong Sacred Hospital, Seoul, South Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John P.","family":"Mayer","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas F.","family":"Covey","sequence":"additional","affiliation":[{"name":"Departments of Developmental Biology, Washington University School of Medicine, Saint Louis, MO"},{"name":"Departments of Psychiatry, Washington University School of Medicine, Saint Louis, MO"},{"name":"Departments of Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, Saint Louis, MO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carmelo","family":"Romano","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tamara","family":"Timic Stamenic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean","family":"Chemin","sequence":"additional","affiliation":[{"name":"Institute of Functional Genomics, Montpellier University, CNRS, INSERM, Montpellier 34000, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel","family":"Bourinet","sequence":"additional","affiliation":[{"name":"Institute of Functional Genomics, Montpellier University, CNRS, INSERM, Montpellier 34000, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gaetan","family":"Poulen","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Gui de Chauliac Hospital, and Donation and Transplantation Coordination Unit, Montpellier University Medical center, Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Longon","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Gui de Chauliac Hospital, and Donation and Transplantation Coordination Unit, Montpellier University Medical center, Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florence","family":"Vachiery-Lahaye","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Gui de Chauliac Hospital, and Donation and Transplantation Coordination Unit, Montpellier University Medical center, Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lue","family":"Bauchet","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Gui de Chauliac Hospital, and Donation and Transplantation Coordination Unit, Montpellier University Medical center, Montpellier, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles F.","family":"Zorumski","sequence":"additional","affiliation":[{"name":"Departments of Psychiatry, Washington University School of Medicine, Saint Louis, MO"},{"name":"Departments of Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, Saint Louis, MO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael H. B.","family":"Stowell","sequence":"additional","affiliation":[{"name":"Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Boulder, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael E.","family":"Hildebrand","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Carleton University, Ottawa Hospital Research Institute ON"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elan Z.","family":"Eisenmesser","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vesna","family":"Jevtovic-Todorovic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"},{"name":"Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, VA"},{"name":"Departments of Psychiatry, Washington University School of Medicine, Saint Louis, MO"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2613-0391","authenticated-orcid":false,"given":"Slobodan M.","family":"Todorovic","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO"},{"name":"Department of Anesthesiology, University of Virginia School of Medicine, Charlottesville, VA"},{"name":"Departments of Psychiatry, Washington University School of Medicine, Saint Louis, MO"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041021434332000_2025.01.03.631165v2.1","doi-asserted-by":"publisher","DOI":"10.3810\/hp.1998.10.114"},{"key":"2026041021434332000_2025.01.03.631165v2.2","doi-asserted-by":"publisher","DOI":"10.1124\/pr.117.014399"},{"key":"2026041021434332000_2025.01.03.631165v2.3","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2018.7104"},{"key":"2026041021434332000_2025.01.03.631165v2.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1507771"},{"key":"2026041021434332000_2025.01.03.631165v2.5","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2711-15.2015"},{"key":"2026041021434332000_2025.01.03.631165v2.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2018.06.002"},{"key":"2026041021434332000_2025.01.03.631165v2.7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2527-05.2005"},{"key":"2026041021434332000_2025.01.03.631165v2.8","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4866-06.2007"},{"key":"2026041021434332000_2025.01.03.631165v2.9","doi-asserted-by":"crossref","unstructured":"Jacus, M. O. , Uebele, V. N. , Renger, J. J. & Todorovic, S. M . Presynaptic CaV3.2 Channels Regulate Excitatory Neurotransmission in Nociceptive Dorsal Horn Neurons. The Journal of Neuroscience 32, 9374 (2012).","DOI":"10.1523\/JNEUROSCI.0068-12.2012"},{"key":"2026041021434332000_2025.01.03.631165v2.10","doi-asserted-by":"crossref","unstructured":"Todorovic, S. M. & Jevtovic-Todorovic, V . T-type voltage-gated calcium channels as targets for the development of novel pain therapies. Br J Pharmacol 163, 484 (2011).","DOI":"10.1111\/j.1476-5381.2011.01256.x"},{"key":"2026041021434332000_2025.01.03.631165v2.11","doi-asserted-by":"publisher","DOI":"10.2337\/db13-0813"},{"key":"2026041021434332000_2025.01.03.631165v2.12","doi-asserted-by":"publisher","DOI":"10.1152\/jn.01031.2007"},{"key":"2026041021434332000_2025.01.03.631165v2.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2014.07.036"},{"key":"2026041021434332000_2025.01.03.631165v2.14","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.b18-00054"},{"key":"2026041021434332000_2025.01.03.631165v2.15","doi-asserted-by":"publisher","DOI":"10.1097\/j.pain.0000000000000774"},{"key":"2026041021434332000_2025.01.03.631165v2.16","doi-asserted-by":"crossref","unstructured":"Joksimovic, S. L. et al. Selective inhibition of CaV3.2 channels reverses hyperexcitability of peripheral nociceptors and alleviates postsurgical pain. Sci Signal 11, (2018).","DOI":"10.1126\/scisignal.aao4425"},{"key":"2026041021434332000_2025.01.03.631165v2.17","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroimage.2016.07.030"},{"key":"2026041021434332000_2025.01.03.631165v2.18","doi-asserted-by":"crossref","unstructured":"Jimenez-Andrade, J. M. et al. Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: Implications for chemical-induced peripheral sensory neuropathies. Mol Pain 4, 10 (2008).","DOI":"10.1186\/1744-8069-4-10"},{"key":"2026041021434332000_2025.01.03.631165v2.19","doi-asserted-by":"publisher","DOI":"10.1124\/mol.104.002402"},{"key":"2026041021434332000_2025.01.03.631165v2.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.bja.2017.12.039"},{"key":"2026041021434332000_2025.01.03.631165v2.21","doi-asserted-by":"publisher","DOI":"10.1124\/mol.111.073205"},{"key":"2026041021434332000_2025.01.03.631165v2.22","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-183X.2006.00268.x"},{"key":"2026041021434332000_2025.01.03.631165v2.23","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2919-09.2009"},{"key":"2026041021434332000_2025.01.03.631165v2.24","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-014-3588-0"},{"key":"2026041021434332000_2025.01.03.631165v2.25","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00338-5"},{"key":"2026041021434332000_2025.01.03.631165v2.26","doi-asserted-by":"crossref","unstructured":"Nelson, M. T. et al. Reducing Agents Sensitize C-Type Nociceptors by Relieving High-Affinity Zinc Inhibition of T-Type Calcium Channels. The Journal of Neuroscience 27, 8250 (2007).","DOI":"10.1523\/JNEUROSCI.1800-07.2007"},{"key":"2026041021434332000_2025.01.03.631165v2.27","doi-asserted-by":"crossref","unstructured":"Chu, X. P. et al. Subunit-Dependent High-Affinity Zinc Inhibition of Acid-Sensing Ion Channels. The Journal of Neuroscience 24, 8678 (2004).","DOI":"10.1523\/JNEUROSCI.2844-04.2004"},{"key":"2026041021434332000_2025.01.03.631165v2.28","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(02)00238-1"},{"key":"2026041021434332000_2025.01.03.631165v2.29","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)81070-3"},{"key":"2026041021434332000_2025.01.03.631165v2.30","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80763-1"},{"key":"2026041021434332000_2025.01.03.631165v2.31","doi-asserted-by":"publisher","DOI":"10.1113\/JP271925"},{"key":"2026041021434332000_2025.01.03.631165v2.32","doi-asserted-by":"crossref","unstructured":"Bal, W. , Soko\u0142owska, M. , Kurowska, E. & Faller, P . Binding of transition metal ions to albumin: sites, affinities and rates. Biochim Biophys Acta 1830, 5444\u20135455 (2013).","DOI":"10.1016\/j.bbagen.2013.06.018"},{"key":"2026041021434332000_2025.01.03.631165v2.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2008.03.001"},{"key":"2026041021434332000_2025.01.03.631165v2.34","doi-asserted-by":"crossref","unstructured":"Schutzer, S. E. et al. Establishing the proteome of normal human cerebrospinal fluid. PLoS One 5, (2010).","DOI":"10.1371\/journal.pone.0010980"},{"key":"2026041021434332000_2025.01.03.631165v2.35","doi-asserted-by":"publisher","DOI":"10.1186\/s41232-017-0053-6"},{"key":"2026041021434332000_2025.01.03.631165v2.36","doi-asserted-by":"publisher","DOI":"10.1007\/s00540-018-2579-4"},{"key":"2026041021434332000_2025.01.03.631165v2.37","doi-asserted-by":"crossref","unstructured":"Psychogios, N. et al. The human serum metabolome. PLoS One 6, (2011).","DOI":"10.1371\/journal.pone.0016957"},{"key":"2026041021434332000_2025.01.03.631165v2.38","doi-asserted-by":"crossref","unstructured":"S\u00e1nchez-Robles, E. M. et al. Monoclonal Antibodies for Chronic Pain Treatment: Present and Future. Int J Mol Sci 22, (2021).","DOI":"10.3390\/ijms221910325"},{"key":"2026041021434332000_2025.01.03.631165v2.39","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-022-00673-7"},{"key":"2026041021434332000_2025.01.03.631165v2.40","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(03)00067-5"},{"key":"2026041021434332000_2025.01.03.631165v2.41","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2005.11.004"},{"key":"2026041021434332000_2025.01.03.631165v2.42","doi-asserted-by":"publisher","DOI":"10.1016\/S0361-9230(01)00454-3"},{"key":"2026041021434332000_2025.01.03.631165v2.43","doi-asserted-by":"publisher","DOI":"10.1007\/s11011-021-00765-w"},{"key":"2026041021434332000_2025.01.03.631165v2.44","doi-asserted-by":"crossref","unstructured":"Lippi, S. L. P. , Neely, C. L. C. & Amaya, A. L . Trace concentrations, heavy implications: Influences of biometals on major brain pathologies of Alzheimer\u2019s disease. Int J Biochem Cell Biol 143, (2022).","DOI":"10.1016\/j.biocel.2021.106136"},{"key":"2026041021434332000_2025.01.03.631165v2.45","doi-asserted-by":"crossref","unstructured":"Weiss, N. & Zamponi, G. W . Genetic T-type calcium channelopathies. J Med Genet 57, 1 (2019).","DOI":"10.1136\/jmedgenet-2019-106163"},{"key":"2026041021434332000_2025.01.03.631165v2.46","doi-asserted-by":"publisher","DOI":"10.1124\/mol.54.5.918"},{"key":"2026041021434332000_2025.01.03.631165v2.47","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-015-0866-z"},{"key":"2026041021434332000_2025.01.03.631165v2.48","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3437"},{"key":"2026041021434332000_2025.01.03.631165v2.49","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2005.06.019"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.01.03.631165","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T04:43:56Z","timestamp":1775882636000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.01.03.631165"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,3]]},"references-count":49,"URL":"https:\/\/doi.org\/10.1101\/2025.01.03.631165","relation":{},"subject":[],"published":{"date-parts":[[2025,1,3]]},"subtype":"preprint"}}