{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T12:42:39Z","timestamp":1792845759609,"version":"4.5.0"},"reference-count":49,"publisher":"Society for Neuroscience","issue":"37","license":[{"start":{"date-parts":[[2017,3,14]],"date-time":"2017-03-14T00:00:00Z","timestamp":1489449600000},"content-version":"vor","delay-in-days":181,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2016,9,14]]},"abstract":"<jats:p>Spinal plasticity, a key process mediating neuropathic pain development, requires ubiquitination-dependent protein turnover. Presynaptic active zone proteins have a crucial role in regulating vesicle exocytosis, which is essential for synaptic plasticity. Nevertheless, the mechanism for ubiquitination-regulated turnover of presynaptic active zone proteins in the progression of spinal plasticity-associated neuropathic pain remains unclear. Here, after research involving Sprague Dawley rats, we reported that spinal nerve ligation (SNL), in addition to causing allodynia, enhances the Rab3-interactive molecule-1\u03b1 (RIM1\u03b1), a major active zone protein presumed to regulate neural plasticity, specifically in the synaptic plasma membranes (SPMs) of the ipsilateral dorsal horn. Spinal RIM1\u03b1-associated allodynia was mediated by Fbxo3, which abates Fbxl2-dependent RIM1\u03b1 ubiquitination. Subsequently, following deubiquitination, enhanced RIM1\u03b1 directly binds to CaV2.2, resulting in increased CaV2.2 expression in the SPMs of the dorsal horn. While exhibiting no effect on Fbxo3\/Fbxl2 signaling, the focal knockdown of spinal RIM1\u03b1 expression reversed the SNL-induced allodynia and increased spontaneous EPSC (sEPSC) frequency by suppressing RIM1\u03b1-facilitated Ca<jats:sub>V<\/jats:sub>2.2 expression in the dorsal horn. Intrathecal applications of BC-1215 (a Fbxo3 activity inhibitor), Fbxl2 mRNA-targeting small-interfering RNA, and \u03c9-conotoxin GVIA (a Ca<jats:sub>V<\/jats:sub>2.2 blocker) attenuated RIM1\u03b1 upregulation, enhanced RIM1\u03b1 expression, and exhibited no effect on RIM1\u03b1 expression, respectively. These results confirm the prediction that spinal presynaptic Fbxo3-dependent Fbxl2 ubiquitination promotes the subsequent RIM1\u03b1\/Ca<jats:sub>V<\/jats:sub>2.2 cascade in SNL-induced neuropathic pain. Our findings identify a role of the presynaptic active zone protein in pain-associated plasticity. That is, RIM1\u03b1-facilitated Ca<jats:sub>V<\/jats:sub>2.2 expression plays a role in the downstream signaling of Fbxo3-dependent Fbxl2 ubiquitination\/degradation to promote spinal plasticity underlying the progression of nociceptive hypersensitivity following neuropathic injury.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Ubiquitination is a well known process required for protein degradation. Studies investigating pain pathology have demonstrated that ubiquitination contributes to chronic pain by regulating the turnover of synaptic proteins. Here, we found that the spinal presynaptic active zone protein Rab3-interactive molecule-1\u03b1 (RIM1\u03b1) participates in neuropathic pain development by binding to and upregulating the expression of Ca<jats:sub>V<\/jats:sub>2.2. In addition, Fbxo3 modifies this pathway by inhibiting Fbxl2-mediated RIM1\u03b1 ubiquitination, suggesting that presynaptic protein ubiquitination makes a crucial contribution to the development of neuropathic pain. Research in this area, now in its infancy, could potentially provide a novel therapeutic strategy for pain relief.<\/jats:p>","DOI":"10.1523\/jneurosci.1732-16.2016","type":"journal-article","created":{"date-parts":[[2016,9,14]],"date-time":"2016-09-14T16:52:50Z","timestamp":1473871970000},"page":"9722-9738","source":"Crossref","is-referenced-by-count":33,"title":["Spinal Fbxo3-Dependent Fbxl2 Ubiquitination of Active Zone Protein RIM1\u03b1 Mediates Neuropathic Allodynia through Ca<sub>V<\/sub>2.2 Activation"],"prefix":"10.1523","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5732-9814","authenticated-orcid":false,"given":"Cheng-Yuan","family":"Lai","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Cheng","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Chun","family":"Hsieh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsueh-Hsiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2384-7856","authenticated-orcid":false,"given":"Jen-Kun","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yat-Pang","family":"Chau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9471-8130","authenticated-orcid":false,"given":"Hsien-Yu","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"393","published-online":{"date-parts":[[2016,9,14]]},"reference":[{"key":"2023041803210648000_36.37.9722.1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27492"},{"key":"2023041803210648000_36.37.9722.2","doi-asserted-by":"crossref","first-page":"243","DOI":"10.3233\/JAD-2004-6305","article-title":"Incubation of nerve endings with a physiological concentration of Abeta1\u201342 activates CaV2.2(N-Type)-voltage operated calcium channels and acutely increases glutamate and noradrenaline release","volume":"6","author":"Bobich","year":"2004","journal-title":"J Alzheimers Dis"},{"key":"2023041803210648000_36.37.9722.3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.26.18290"},{"key":"2023041803210648000_36.37.9722.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.05.014"},{"key":"2023041803210648000_36.37.9722.5","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2565"},{"key":"2023041803210648000_36.37.9722.6","first-page":"35","article-title":"Segmental spinal nerve ligation model of neuropathic pain","volume":"99","author":"Chung","year":"2004","journal-title":"Methods Mol Med"},{"key":"2023041803210648000_36.37.9722.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00687-1"},{"key":"2023041803210648000_36.37.9722.8","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M100929200"},{"key":"2023041803210648000_36.37.9722.9","doi-asserted-by":"publisher","DOI":"10.1038\/nn1013"},{"key":"2023041803210648000_36.37.9722.10","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201206063"},{"key":"2023041803210648000_36.37.9722.11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.187757"},{"key":"2023041803210648000_36.37.9722.12","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-014-1476-4"},{"key":"2023041803210648000_36.37.9722.13","doi-asserted-by":"publisher","DOI":"10.1038\/42954"},{"key":"2023041803210648000_36.37.9722.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.12.014"},{"key":"2023041803210648000_36.37.9722.15","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00488.2014"},{"key":"2023041803210648000_36.37.9722.16","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80188-9"},{"key":"2023041803210648000_36.37.9722.17","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(02)00667-0"},{"key":"2023041803210648000_36.37.9722.18","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2013.10.026"},{"key":"2023041803210648000_36.37.9722.19","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12251"},{"key":"2023041803210648000_36.37.9722.20","doi-asserted-by":"publisher","DOI":"10.1042\/BST0331345"},{"key":"2023041803210648000_36.37.9722.21","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3235-08.2008"},{"key":"2023041803210648000_36.37.9722.22","doi-asserted-by":"publisher","DOI":"10.1038\/ng0197-70"},{"key":"2023041803210648000_36.37.9722.23","doi-asserted-by":"publisher","DOI":"10.1016\/j.pain.2005.05.035"},{"key":"2023041803210648000_36.37.9722.24","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0000000000000809"},{"key":"2023041803210648000_36.37.9722.25","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2301-15.2015"},{"key":"2023041803210648000_36.37.9722.26","doi-asserted-by":"publisher","DOI":"10.1111\/jpi.12307"},{"key":"2023041803210648000_36.37.9722.27","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3959(99)00211-0"},{"key":"2023041803210648000_36.37.9722.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2012.06.074"},{"key":"2023041803210648000_36.37.9722.29","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300456"},{"key":"2023041803210648000_36.37.9722.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2015.02.011"},{"key":"2023041803210648000_36.37.9722.31","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5126-06.2007"},{"key":"2023041803210648000_36.37.9722.32","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3712-09.2010"},{"key":"2023041803210648000_36.37.9722.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2014.05.103"},{"key":"2023041803210648000_36.37.9722.34","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1523\/JNEUROSCI.23-07-02517.2003","article-title":"Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons","volume":"23","author":"Sch\u00e4fers","year":"2003","journal-title":"J Neurosci"},{"key":"2023041803210648000_36.37.9722.35","doi-asserted-by":"publisher","DOI":"10.1038\/415321a"},{"key":"2023041803210648000_36.37.9722.36","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601425"},{"key":"2023041803210648000_36.37.9722.37","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201301011"},{"key":"2023041803210648000_36.37.9722.38","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(03)00338-5"},{"key":"2023041803210648000_36.37.9722.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2005.04.005"},{"key":"2023041803210648000_36.37.9722.40","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M103337200"},{"key":"2023041803210648000_36.37.9722.41","doi-asserted-by":"publisher","DOI":"10.1038\/41580"},{"key":"2023041803210648000_36.37.9722.42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M909008199"},{"key":"2023041803210648000_36.37.9722.43","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2012.250522"},{"key":"2023041803210648000_36.37.9722.44","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.06.052"},{"key":"2023041803210648000_36.37.9722.45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0017317"},{"key":"2023041803210648000_36.37.9722.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2005.07.008"},{"key":"2023041803210648000_36.37.9722.47","doi-asserted-by":"publisher","DOI":"10.1016\/S0960-9822(03)00332-4"},{"key":"2023041803210648000_36.37.9722.48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5857-09.2010"},{"key":"2023041803210648000_36.37.9722.49","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3959(83)90201-4"}],"container-title":["The Journal of Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1523\/JNEUROSCI.1732-16.2016","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T10:41:46Z","timestamp":1681814506000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.jneurosci.org\/lookup\/doi\/10.1523\/JNEUROSCI.1732-16.2016"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,9,14]]},"references-count":49,"journal-issue":{"issue":"37","published-online":{"date-parts":[[2016,9,14]]},"published-print":{"date-parts":[[2016,9,14]]}},"alternative-id":["10.1523\/JNEUROSCI.1732-16.2016"],"URL":"https:\/\/doi.org\/10.1523\/jneurosci.1732-16.2016","relation":{},"ISSN":["0270-6474","1529-2401"],"issn-type":[{"value":"0270-6474","type":"print"},{"value":"1529-2401","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,9,14]]}}}