{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T10:06:15Z","timestamp":1789121175471,"version":"build-2803163510"},"reference-count":95,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Innovation of Science and Technology 2030-Major Project \"platform of nonhuman primate models\"","award":["2021ZD0200900"],"award-info":[{"award-number":["2021ZD0200900"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82271269"],"award-info":[{"award-number":["82271269"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82271269"],"award-info":[{"award-number":["82271269"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82021001"],"award-info":[{"award-number":["82021001"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"award":["82021001"],"award-info":[{"award-number":["82021001"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>During sustained activity, voltage-gated sodium (Nav) channels enter a slow-inactivated state to limit cellular hyperexcitability. Disruption of this regulatory process has been implicated in skeletal, cardiac, and neurological disorders. While the kinetics of this process are well characterized, its endogenous modulators remain unclear. Here, we identify Proline-Rich Transmembrane Protein 2 (PRRT2) as a native regulator of Nav channel slow inactivation. We show that PRRT2 facilitates the entry of Nav channels into the slow-inactivated state and delays their recovery, a regulatory effect conserved from zebrafish to humans. PRRT2 forms molecular complexes with Nav channels both in vitro and in vivo. In the mouse cortex, PRRT2 deficiency impairs the slow inactivation of Nav channels in neuronal axons, leading to reduced cortical resilience in response to hyperexcitable challenges. Together, these findings establish PRRT2 as a physiological modulator of Nav channel slow inactivation and reveal a mechanism that supports cortical resilience to pathological perturbations.<\/jats:p>","DOI":"10.7554\/elife.109327","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T14:30:24Z","timestamp":1766068224000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.109327","source":"Crossref","is-referenced-by-count":0,"title":["PRRT2 as an auxiliary regulator of Nav channel slow inactivation"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1456-2517","authenticated-orcid":true,"given":"Bin","family":"Lu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Chinese Academy of Sciences","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2236-8415","authenticated-orcid":true,"given":"Qi-Wu","family":"Xu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4050-8486","authenticated-orcid":true,"given":"Jing","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3387-7579","authenticated-orcid":true,"given":"Xue-Mei","family":"Wu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Chinese Academy of Sciences","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/030bhh786","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Science and Technology, ShanghaiTech University","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3342-9877","authenticated-orcid":true,"given":"Jun-Yan","family":"He","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Chinese Academy of Sciences","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1124-7726","authenticated-orcid":true,"given":"Jing-Qiu","family":"Peng","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Chinese Academy of Sciences","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/030bhh786","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Science and Technology, ShanghaiTech University","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1840-8411","authenticated-orcid":true,"given":"Guang","family":"Yang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Chinese Academy of Sciences","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-5401-4923","authenticated-orcid":true,"given":"Ke-Xian","family":"Li","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013q1eq08","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Neurology, Zhongshan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6846-883X","authenticated-orcid":true,"given":"Ling","family":"Zhuang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Chinese Academy of Sciences","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"resources","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-1796-1443","authenticated-orcid":true,"given":"Yu-Xian","family":"Zhang","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Chinese Academy of Sciences","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-572X","authenticated-orcid":true,"given":"Zhi-Ying","family":"Wu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/059cjpv64","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine and Zhejiang Key Laboratory of Rare Diseases for Precision Medicine and Clinical Translation","place":["Hangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7727-8412","authenticated-orcid":true,"given":"Zhi-Qi","family":"Xiong","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/034t30j35","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Excellence in Brain Science and Intelligence Technology (Institute of Neuroscience), Chinese Academy of Sciences","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/05qbk4x57","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Chinese Academy of Sciences","place":["Beijing, China"]},{"id":[{"id":"https:\/\/ror.org\/030bhh786","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Life Science and Technology, ShanghaiTech University","place":["Shanghai, China"]},{"id":[{"id":"https:\/\/ror.org\/0551a0y31","id-type":"ROR","asserted-by":"publisher"}],"name":"Shanghai Center for Brain Science and Brain-Inspired Technology","place":["Shanghai, China"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1085\/jgp.70.5.567","type":"journal-article","article-title":"Inactivation of the sodium channel II Gating current experiments","volume":"70","author":"Armstrong","year":"1977","journal-title":"The Journal of General Physiology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1113\/jphysiol.1996.sp021503","type":"journal-article","article-title":"External pore residue mediates slow inactivation in mu 1 rat skeletal muscle sodium channels","volume":"494 (Pt 2)","author":"Balser","year":"1996","journal-title":"The Journal of Physiology"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"1127","DOI":"10.1152\/jn.01232.2007","type":"journal-article","article-title":"Space-clamp problems when voltage clamping neurons expressing voltage-gated conductances","volume":"99","author":"Bar-Yehuda","year":"2008","journal-title":"Journal of Neurophysiology"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"1266","DOI":"10.1212\/wnl.58.8.1266","type":"journal-article","article-title":"Impairment of slow inactivation as a common mechanism for periodic paralysis in DIIS4-S5","volume":"58","author":"Bendahhou","year":"2002","journal-title":"Neurology"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1085\/jgp.70.5.549","type":"journal-article","article-title":"Inactivation of the sodium channel I sodium current experiments","volume":"70","author":"Bezanilla","year":"1977","journal-title":"The Journal of General Physiology"},{"key":"bib6","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2021.105275","type":"journal-article","article-title":"Increased responsiveness at the cerebellar input stage in the PRRT2 knockout model of paroxysmal kinesigenic dyskinesia","volume":"152","author":"Binda","year":"2021","journal-title":"Neurobiology of Disease"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1016\/j.clinph.2003.11.023","type":"journal-article","article-title":"Properties of after-discharges from cortical electrical stimulation in focal epilepsies","volume":"115","author":"Blume","year":"2004","journal-title":"Clinical Neurophysiology"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1007\/164_2017_52","type":"journal-article","article-title":"Sodium channelopathies of skeletal muscle","volume":"246","author":"Cannon","year":"2018","journal-title":"Handb Exp Pharmacol"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1124\/pr.57.4.4","type":"journal-article","article-title":"International union of pharmacology","volume":"57","author":"Catterall","year":"2005","journal-title":"Pharmacological Reviews"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"1314","DOI":"10.1038\/s41589-020-0644-4","type":"journal-article","article-title":"The conformational cycle of a prototypical voltage-gated sodium channel","volume":"16","author":"Catterall","year":"2020","journal-title":"Nature Chemical Biology"},{"key":"bib11","doi-asserted-by":"publisher","DOI":"10.1080\/19336950.2023.2281714","type":"journal-article","article-title":"Voltage gated sodium and calcium channels: discovery, structure, function, and Pharmacology","volume":"17","author":"Catterall","year":"2023","journal-title":"Channels"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1016\/j.chembiol.2024.07.010","type":"journal-article","article-title":"The chemistry of electrical signaling in sodium channels from bacteria and beyond","volume":"31","author":"Catterall","year":"2024","journal-title":"Cell Chemical Biology"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"C1895","DOI":"10.1152\/ajpcell.00377.2007","type":"journal-article","article-title":"Relative resistance to slow inactivation of human cardiac Na+ channel hNav1.5 is reversed by lysine or glutamine substitution at V930 in D2-S6","volume":"293","author":"Chancey","year":"2007","journal-title":"American Journal of Physiology. Cell Physiology"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1085\/jgp.201812118","type":"journal-article","article-title":"The voltage-gated sodium channel pore exhibits conformational flexibility during slow inactivation","volume":"150","author":"Chatterjee","year":"2018","journal-title":"The Journal of General Physiology"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.neuron.2006.01.009","type":"journal-article","article-title":"Neuromodulation of Na+ channel slow inactivation via cAMP-dependent protein kinase and protein kinase C","volume":"49","author":"Chen","year":"2006","journal-title":"Neuron"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1038\/ng.1008","type":"journal-article","article-title":"Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia","volume":"43","author":"Chen","year":"2011","journal-title":"Nature Genetics"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1016\/j.celrep.2017.12.056","type":"journal-article","article-title":"PRRT2 regulates synaptic fusion by directly modulating SNARE complex assembly","volume":"22","author":"Coleman","year":"2018","journal-title":"Cell Reports"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/S0006-3495(96)79219-6","type":"journal-article","article-title":"Impaired slow inactivation in mutant sodium channels","volume":"71","author":"Cummins","year":"1996","journal-title":"Biophysical Journal"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1111\/j.1600-0854.2007.00673.x","type":"journal-article","article-title":"Trafficking and cellular distribution of voltage-gated sodium channels","volume":"9","author":"Cusdin","year":"2008","journal-title":"Traffic"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.conb.2018.09.001","type":"journal-article","article-title":"Plasticity of intrinsic neuronal excitability","volume":"54","author":"Debanne","year":"2019","journal-title":"Current Opinion in Neurobiology"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"S97","DOI":"10.1097\/j.pain.0000000000000854","type":"journal-article","article-title":"Sodium channels in pain disorders: pathophysiology and prospects for treatment","volume":"158 Suppl 1","author":"Dib-Hajj","year":"2017","journal-title":"Pain"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"3695","DOI":"10.1113\/jphysiol.2010.192559","type":"journal-article","article-title":"Long-term inactivation particle for voltage-gated sodium channels","volume":"588","author":"Dover","year":"2010","journal-title":"The Journal of Physiology"},{"key":"bib23","doi-asserted-by":"publisher","DOI":"10.3390\/epigenomes4010001","type":"journal-article","article-title":"Epigenetics of skeletal muscle-associated genes in the ASB, LRRC, TMEM, and OSBPL gene families","volume":"4","author":"Ehrlich","year":"2020","journal-title":"Epigenomes"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"1650","DOI":"10.1111\/j.1528-1167.2010.02640.x","type":"journal-article","article-title":"Sodium channel SCN1A and epilepsy: mutations and mechanisms","volume":"51","author":"Escayg","year":"2010","journal-title":"Epilepsia"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"3098","DOI":"10.1016\/S0006-3495(96)79504-8","type":"journal-article","article-title":"Interaction between fast and slow inactivation in Skm1 sodium channels","volume":"71","author":"Featherstone","year":"1996","journal-title":"Biophysical Journal"},{"key":"bib26","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109248","type":"journal-article","article-title":"PRRT2 modulates presynaptic Ca2+ influx by interacting with P\/Q-type channels","volume":"35","author":"Ferrante","year":"2021","journal-title":"Cell Reports"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1113\/jphysiol.1996.sp021366","type":"journal-article","article-title":"Slow inactivation of Na+ current and slow cumulative spike adaptation in mouse and guinea-pig neocortical neurones in slices","volume":"493 (Pt 1)","author":"Fleidervish","year":"1996","journal-title":"The Journal of Physiology"},{"key":"bib28","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.104632","type":"journal-article","article-title":"The intramembrane COOH-terminal domain of PRRT2 regulates voltage-dependent Na+ channels","volume":"299","author":"Franchi","year":"2023","journal-title":"The Journal of Biological Chemistry"},{"key":"bib29","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adf3885","type":"journal-article","article-title":"Sodium channel endocytosis drives axon initial segment plasticity","volume":"9","author":"Fr\u00e9al","year":"2023","journal-title":"Science Advances"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1093\/brain\/awy051","type":"journal-article","article-title":"PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2\/1.6 activity","volume":"141","author":"Fruscione","year":"2018","journal-title":"Brain"},{"key":"bib31","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201912434","type":"journal-article","article-title":"An interaction between the III-IV linker and CTD in NaV1.5 confers regulation of inactivation by CaM and FHF","volume":"152","author":"Gade","year":"2020","journal-title":"The Journal of General Physiology"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"4375","DOI":"10.1113\/JP281834","type":"journal-article","article-title":"Enhanced slow inactivation contributes to dysfunction of a recurrent SCN2A mutation associated with developmental and epileptic encephalopathy","volume":"599","author":"Ganguly","year":"2021","journal-title":"The Journal of Physiology"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1152\/jn.00457.2022","type":"journal-article","article-title":"Nav1.7 P610T mutation in two siblings with persistent ocular pain after corneal axon transection: impaired slow inactivation and hyperexcitable trigeminal neurons","volume":"129","author":"Ghovanloo","year":"2023","journal-title":"Journal of Neurophysiology"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"17883","DOI":"10.1074\/jbc.M109.001842","type":"journal-article","article-title":"Crystal structure of a fibroblast growth factor homologous factor (FHF) defines a conserved surface on FHFs for binding and modulation of voltage-gated sodium channels","volume":"284","author":"Goetz","year":"2009","journal-title":"The Journal of Biological Chemistry"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1146\/annurev.physiol.63.1.871","type":"journal-article","article-title":"Resurgence of sodium channel research","volume":"63","author":"Goldin","year":"2001","journal-title":"Annual Review of Physiology"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1016\/s0959-4388(03)00065-5","type":"journal-article","article-title":"Mechanisms of sodium channel inactivation","volume":"13","author":"Goldin","year":"2003","journal-title":"Current Opinion in Neurobiology"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1212\/wnl.52.7.1447","type":"journal-article","article-title":"Defective slow inactivation of sodium channels contributes to familial periodic paralysis","volume":"52","author":"Hayward","year":"1999","journal-title":"Neurology"},{"key":"bib38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0085188","type":"journal-article","article-title":"Functional expression of Rat Nav1.6 voltage-gated sodium channels in HEK293 cells: modulation by the auxiliary \u03b21 subunit","volume":"9","author":"He","year":"2014","journal-title":"PLOS ONE"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"S68","DOI":"10.1111\/epi.14731","type":"journal-article","article-title":"SCN2A channelopathies: Mechanisms and models","volume":"60 Suppl 3","author":"Hedrich","year":"2019","journal-title":"Epilepsia"},{"key":"bib40","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.102816","type":"journal-article","article-title":"The fates of internalized NaV1.7 channels in sensory neurons: Retrograde cotransport with other ion channels, axon-specific recycling, and degradation","volume":"299","author":"Higerd-Rusli","year":"2023","journal-title":"The Journal of Biological Chemistry"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1113\/jphysiol.1952.sp004764","type":"journal-article","article-title":"A quantitative description of membrane current and its application to conduction and excitation in nerve","volume":"117","author":"Hodgkin","year":"1952","journal-title":"The Journal of Physiology"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1007\/s12264-012-1247-1","type":"journal-article","article-title":"Axonal bleb recording","volume":"28","author":"Hu","year":"2012","journal-title":"Neuroscience Bulletin"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1126\/science.1375395","type":"journal-article","article-title":"Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel","volume":"256","author":"Isom","year":"1992","journal-title":"Science"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.cell.2019.11.041","type":"journal-article","article-title":"Structure of the cardiac sodium channel","volume":"180","author":"Jiang","year":"2020","journal-title":"Cell"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/164_2021_457","type":"journal-article","article-title":"Kv7 channels and excitability disorders","volume":"267","author":"Jones","year":"2021","journal-title":"Handb Exp Pharmacol"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.1152\/jn.00276.2011","type":"journal-article","article-title":"Decreased afferent excitability contributes to synaptic depression during high-frequency stimulation in hippocampal area CA1","volume":"108","author":"Kim","year":"2012","journal-title":"Journal of Neurophysiology"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.celrep.2011.11.001","type":"journal-article","article-title":"Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions","volume":"1","author":"Lee","year":"2012","journal-title":"Cell Reports"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"5482","DOI":"10.1523\/JNEUROSCI.0086-22.2022","type":"journal-article","article-title":"Direct observation of compartment-specific localization and dynamics of voltage-gated sodium channels","volume":"42","author":"Liu","year":"2022","journal-title":"The Journal of Neuroscience"},{"key":"bib49","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109743","type":"journal-article","article-title":"Cerebellar spreading depolarization mediates paroxysmal movement disorder","volume":"36","author":"Lu","year":"2021","journal-title":"Cell Reports"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"7117","DOI":"10.1523\/JNEUROSCI.16-22-07117.1996","type":"journal-article","article-title":"Molecular determinants of beta 1 subunit-induced gating modulation in voltage-dependent Na+ channels","volume":"16","author":"Makita","year":"1996","journal-title":"The Journal of Neuroscience"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1152\/physrev.00025.2020","type":"journal-article","article-title":"Sodium channelopathies of skeletal muscle and brain","volume":"101","author":"Mantegazza","year":"2021","journal-title":"Physiological Reviews"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"640","DOI":"10.1038\/s41583-023-00730-9","type":"journal-article","article-title":"A biophysical perspective on the resilience of neuronal excitability across timescales","volume":"24","author":"Marom","year":"2023","journal-title":"Nature Reviews. Neuroscience"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1073\/pnas.2235688100","type":"journal-article","article-title":"Electroporation and RNA interference in the rodent retina in vivo and in vitro","volume":"101","author":"Matsuda","year":"2004","journal-title":"PNAS"},{"key":"bib54","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1038\/s41583-020-00418-4","type":"journal-article","article-title":"Sodium channelopathies in neurodevelopmental disorders","volume":"22","author":"Meisler","year":"2021","journal-title":"Nature Reviews. Neuroscience"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1111\/j.1749-6632.1999.tb11280.x","type":"journal-article","article-title":"Slow sodium channel inactivation in CA1 pyramidal cells","volume":"868","author":"Mickus","year":"1999","journal-title":"Annals of the New York Academy of Sciences"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1111\/j.1528-1167.2008.01619.x","type":"journal-article","article-title":"Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal-infantile seizures","volume":"49","author":"Misra","year":"2008","journal-title":"Epilepsia"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1085\/jgp.115.6.707","type":"journal-article","article-title":"Role of domain 4 in sodium channel slow inactivation","volume":"115","author":"Mitrovic","year":"2000","journal-title":"The Journal of General Physiology"},{"key":"bib58","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.166967","type":"journal-article","article-title":"Structural pharmacology of voltage-gated sodium channels","volume":"433","author":"Noreng","year":"2021","journal-title":"Journal of Molecular Biology"},{"key":"bib59","doi-asserted-by":"publisher","first-page":"34226","DOI":"10.1074\/jbc.M303183200","type":"journal-article","article-title":"Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs","volume":"278","author":"Olsen","year":"2003","journal-title":"The Journal of Biological Chemistry"},{"key":"bib60","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.mce.2007.06.005","type":"journal-article","article-title":"Characterization of Tusc5, an adipocyte gene co-expressed in peripheral neurons","volume":"276","author":"Oort","year":"2007","journal-title":"Molecular and Cellular Endocrinology"},{"key":"bib61","doi-asserted-by":"publisher","first-page":"1309","DOI":"10.1126\/science.aaw2999","type":"journal-article","article-title":"Molecular basis for pore blockade of human Na(+) channel Na(v)1.2 by the mu-conotoxin KIIIA","volume":"363","author":"Pan","year":"2019","journal-title":"Science"},{"key":"bib62","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2100066118","type":"journal-article","article-title":"Comparative structural analysis of human Na(v)1.1 and Na(v)1.5 reveals mutational hotspots for sodium channelopathies","volume":"118","author":"Pan","year":"2021","journal-title":"PNAS"},{"key":"bib63","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1085\/jgp.201812149","type":"journal-article","article-title":"Progress in understanding slow inactivation speeds up","volume":"150","author":"Payandeh","year":"2018","journal-title":"The Journal of General Physiology"},{"key":"bib64","doi-asserted-by":"publisher","first-page":"4099","DOI":"10.1113\/jphysiol.2013.256461","type":"journal-article","article-title":"Cardiac sodium channelopathy associated with SCN5A mutations: electrophysiological, molecular and genetic aspects","volume":"591","author":"Remme","year":"2013","journal-title":"The Journal of Physiology"},{"key":"bib65","doi-asserted-by":"publisher","first-page":"e51","DOI":"10.1212\/WNL.0000000000012947","type":"journal-article","article-title":"Hemiplegic migraine associated With PRRT2 variations: a clinical and genetic study","volume":"98","author":"Riant","year":"2022","journal-title":"Neurology"},{"key":"bib66","doi-asserted-by":"publisher","first-page":"2945","DOI":"10.1016\/S0006-3495(98)78001-4","type":"journal-article","article-title":"Slow inactivation in human cardiac sodium channels","volume":"74","author":"Richmond","year":"1998","journal-title":"Biophysical Journal"},{"key":"bib67","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1113\/jphysiol.1978.sp012485","type":"journal-article","article-title":"Slow inactivation of the sodium conductance in squid giant axons. Pronase resistance","volume":"283","author":"Rudy","year":"1978","journal-title":"The Journal of Physiology"},{"key":"bib68","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0031961","type":"journal-article","article-title":"The dispanins: a novel gene family of ancient origin that contains 14 human members","volume":"7","author":"S\u00e4llman Alm\u00e9n","year":"2012","journal-title":"PLOS ONE"},{"key":"bib69","doi-asserted-by":"publisher","DOI":"10.12688\/wellcomeopenres.17090.1","type":"journal-article","article-title":"Tools for analysis and conditional deletion of subsets of sensory neurons","volume":"6","author":"Santana-Varela","year":"2021","journal-title":"Wellcome Open Research"},{"key":"bib70","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/j.mce.2006.08.007","type":"journal-article","article-title":"Molecular cloning and characterization of rat brain endothelial cell derived gene-1 (tumor suppressor candidate 5) expressing abundantly in adipose tissues","volume":"263","author":"Shibata","year":"2007","journal-title":"Molecular and Cellular Endocrinology"},{"key":"bib71","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/978-3-642-41588-3_3","type":"journal-article","article-title":"Slow inactivation of Na(+) channels","volume":"221","author":"Silva","year":"2014","journal-title":"Handb Exp Pharmacol"},{"key":"bib72","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/cr.2017.128","type":"journal-article","article-title":"PRRT2 deficiency induces paroxysmal kinesigenic dyskinesia by regulating synaptic transmission in cerebellum","volume":"28","author":"Tan","year":"2018","journal-title":"Cell Research"},{"key":"bib73","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202313375","type":"journal-article","article-title":"Epilepsy-associated SCN2A (NaV1.2) variants exhibit diverse and complex functional properties","volume":"155","author":"Thompson","year":"2023","journal-title":"The Journal of General Physiology"},{"key":"bib74","doi-asserted-by":"publisher","first-page":"1335","DOI":"10.1016\/S0006-3495(99)77296-6","type":"journal-article","article-title":"Ultra-slow inactivation in mu1 Na+ channels is produced by a structural rearrangement of the outer vestibule","volume":"76","author":"Todt","year":"1999","journal-title":"Biophysical Journal"},{"key":"bib75","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1038\/s41583-025-00917-2","type":"journal-article","article-title":"Sculpting excitable membranes: voltage-gated ion channel delivery and distribution","volume":"26","author":"Tyagi","year":"2025","journal-title":"Nature Reviews. Neuroscience"},{"key":"bib76","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1146\/annurev.bb.06.060177.000255","type":"journal-article","article-title":"Ionic channels and gating currents in excitable membranes","volume":"6","author":"Ulbricht","year":"1977","journal-title":"Annual Review of Biophysics and Bioengineering"},{"key":"bib77","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.celrep.2016.03.005","type":"journal-article","article-title":"PRRT2 is a key component of the Ca2+-dependent neurotransmitter release machinery","volume":"15","author":"Valente","year":"2016","journal-title":"Cell Reports"},{"key":"bib78","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1007\/s12035-022-03112-x","type":"journal-article","article-title":"A push-pull mechanism between PRRT2 and \u03b24-subunit differentially regulates membrane exposure and biophysical properties of NaV1.2 sodium channels","volume":"60","author":"Valente","year":"2023","journal-title":"Molecular Neurobiology"},{"key":"bib79","doi-asserted-by":"publisher","first-page":"16126","DOI":"10.1523\/JNEUROSCI.1271-14.2014","type":"journal-article","article-title":"Fast-onset long-term open-state block of sodium channels by A-type FHFs mediates classical spike accommodation in hippocampal pyramidal neurons","volume":"34","author":"Venkatesan","year":"2014","journal-title":"The Journal of Neuroscience"},{"key":"bib80","doi-asserted-by":"publisher","first-page":"1384","DOI":"10.1016\/S0006-3495(99)76987-0","type":"journal-article","article-title":"Structural determinants of slow inactivation in human cardiac and skeletal muscle sodium channels","volume":"77","author":"Vilin","year":"1999","journal-title":"Biophysical Journal"},{"key":"bib81","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1385\/CBB:35:2:171","type":"journal-article","article-title":"Slow inactivation in voltage-gated sodium channels: molecular substrates and contributions to channelopathies","volume":"35","author":"Vilin","year":"2001","journal-title":"Cell Biochemistry and Biophysics"},{"key":"bib82","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/0014-5793(93)80871-q","type":"journal-article","article-title":"Modulation of the skeletal muscle sodium channel alpha-subunit by the beta 1-subunit","volume":"336","author":"Wallner","year":"1993","journal-title":"FEBS Letters"},{"key":"bib83","doi-asserted-by":"publisher","first-page":"1633","DOI":"10.1016\/S0006-3495(97)78809-X","type":"journal-article","article-title":"A mutation in segment I-S6 alters slow inactivation of sodium channels","volume":"72","author":"Wang","year":"1997","journal-title":"Biophysical Journal"},{"key":"bib84","doi-asserted-by":"publisher","first-page":"E37","DOI":"10.1161\/01.res.87.8.e37","type":"journal-article","article-title":"Enhanced Na(+) channel intermediate inactivation in Brugada syndrome","volume":"87","author":"Wang","year":"2000","journal-title":"Circulation Research"},{"key":"bib85","doi-asserted-by":"publisher","first-page":"3493","DOI":"10.1093\/brain\/awr289","type":"journal-article","article-title":"Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias","volume":"134","author":"Wang","year":"2011","journal-title":"Brain"},{"key":"bib86","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1016\/j.molmed.2013.04.003","type":"journal-article","article-title":"Painful Na-channelopathies: an expanding universe","volume":"19","author":"Waxman","year":"2013","journal-title":"Trends in Molecular Medicine"},{"key":"bib87","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1007\/s00424-008-0600-8","type":"journal-article","article-title":"Slow inactivation of the NaV1.4 sodium channel in mammalian cells is impeded by co-expression of the beta1 subunit","volume":"457","author":"Webb","year":"2009","journal-title":"Pflugers Archiv"},{"key":"bib88","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.858348","type":"journal-article","article-title":"Druggability of voltage-gated sodium channels-exploring old and new drug receptor sites","volume":"13","author":"Wisedchaisri","year":"2022","journal-title":"Frontiers in Pharmacology"},{"key":"bib89","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adp2377","type":"journal-article","article-title":"Aberrant outputs of glutamatergic neurons in deep cerebellar nuclei mediate dystonic movements","volume":"11","author":"Wu","year":"2025","journal-title":"Science Advances"},{"key":"bib90","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1113\/jphysiol.2006.115105","type":"journal-article","article-title":"A conserved ring of charge in mammalian Na+ channels: a molecular regulator of the outer pore conformation during slow inactivation","volume":"576","author":"Xiong","year":"2006","journal-title":"The Journal of Physiology"},{"key":"bib91","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.neuroscience.2007.05.038","type":"journal-article","article-title":"Generalized epilepsy with febrile seizures plus-associated sodium channel beta1 subunit mutations severely reduce beta subunit-mediated modulation of sodium channel function","volume":"148","author":"Xu","year":"2007","journal-title":"Neuroscience"},{"key":"bib92","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.neures.2021.11.005","type":"journal-article","article-title":"The diffuse distribution of Nav1.2 on mid-axonal regions is a marker for unmyelinated fibers in the central nervous system","volume":"177","author":"Yamano","year":"2022","journal-title":"Neuroscience Research"},{"key":"bib93","doi-asserted-by":"publisher","first-page":"1956","DOI":"10.1038\/nprot.2014.134","type":"journal-article","article-title":"Generating genetically modified mice using CRISPR\/Cas-mediated genome engineering","volume":"9","author":"Yang","year":"2014","journal-title":"Nature Protocols"},{"key":"bib94","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1038\/nn1754","type":"journal-article","article-title":"Reduced sodium current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy","volume":"9","author":"Yu","year":"2006","journal-title":"Nature Neuroscience"},{"key":"bib95","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1016\/j.cub.2023.03.043","type":"journal-article","article-title":"Sodium channel slow inactivation normalizes firing in axons with uneven conductance distributions","volume":"33","author":"Zang","year":"2023","journal-title":"Current Biology"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/109327\/elife-109327-v1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/109327\/elife-109327-v1.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/109327","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T09:05:43Z","timestamp":1789117543000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/109327"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,11]]},"references-count":95,"alternative-id":["10.7554\/eLife.109327"],"URL":"https:\/\/doi.org\/10.7554\/elife.109327","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.09.27.678785","asserted-by":"subject"}],"is-same-as":[{"id-type":"doi","id":"10.7554\/eLife.109327.4","asserted-by":"subject"}],"is-version-of":[{"id-type":"doi","id":"10.7554\/eLife.109327.1","asserted-by":"subject"},{"id-type":"doi","id":"10.7554\/eLife.109327.2","asserted-by":"subject"},{"id-type":"doi","id":"10.7554\/eLife.109327.3","asserted-by":"subject"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,11]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"RP109327"}}