{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:27:24Z","timestamp":1790843244126,"version":"4.1.0"},"reference-count":45,"publisher":"The Company of Biologists","issue":"2","license":[{"start":{"date-parts":[[2019,1,14]],"date-time":"2019-01-14T00:00:00Z","timestamp":1547424000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"name":"Association pour la Recherche sur la Scl\u00e9rose en Plaques"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,1,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The distribution of the voltage-gated Kv1 K+ channels at the axon initial segment (AIS) influences neuronal intrinsic excitability. The Kv1.1 and Kv1.2 (also known as KCNA1 and KCNA2, respectively) subunits are associated with cell adhesion molecules (CAMs), including Caspr2 (also known as CNTNAP2) and LGI1, which are implicated in autoimmune and genetic neurological diseases with seizures. In particular, mutations in the LGI1 gene cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). Here, by using rat hippocampal neurons in culture, we showed that LGI1 is recruited to the AIS where it colocalizes with ADAM22 and Kv1 channels. Strikingly, the missense mutations S473L and R474Q of LGI1 identified in ADLTE prevent its association with ADAM22 and enrichment at the AIS. Moreover, we observed that ADAM22 and ADAM23 modulate the trafficking of LGI1, and promote its ER export and expression at the overall neuronal cell surface. Live-cell imaging indicated that LGI1 is co-transported in axonal vesicles with ADAM22 and ADAM23. Finally, we showed that ADAM22 and ADAM23 also associate with Caspr2 and TAG-1 (also known as CNTN2) to be selectively targeted to different axonal sub-regions. Hence, the combinatorial expression of Kv1-associated CAMs may be critical to tune intrinsic excitability in physiological and epileptogenic contexts.<\/jats:p>","DOI":"10.1242\/jcs.219774","type":"journal-article","created":{"date-parts":[[2018,12,31]],"date-time":"2018-12-31T08:25:11Z","timestamp":1546244711000},"source":"Crossref","is-referenced-by-count":58,"title":["ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment"],"prefix":"10.1242","volume":"132","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3371-6123","authenticated-orcid":false,"given":"Bruno","family":"Hivert","sequence":"first","affiliation":[{"name":"INMED, Aix Marseille Universit\u00e9, INSERM UMR1249 , F-13273 Marseille , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1445-2940","authenticated-orcid":false,"given":"Laur\u00e8ne","family":"Marien","sequence":"additional","affiliation":[{"name":"INMED, Aix Marseille Universit\u00e9, INSERM UMR1249 , F-13273 Marseille , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3045-6853","authenticated-orcid":false,"given":"Komlan Nassirou","family":"Agbam","sequence":"additional","affiliation":[{"name":"INMED, Aix Marseille Universit\u00e9, INSERM UMR1249 , F-13273 Marseille , France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1718-0533","authenticated-orcid":false,"given":"Catherine","family":"Faivre-Sarrailh","sequence":"additional","affiliation":[{"name":"INMED, Aix Marseille Universit\u00e9, INSERM UMR1249 , F-13273 Marseille , France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2019,1,16]]},"reference":[{"key":"2024061318201068600_JCS219774C1","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.celrep.2012.05.018","article-title":"Differential trafficking of transport vesicles contributes to the localization of dendritic proteins","volume":"2","author":"Al-Bassam","year":"2012","journal-title":"Cell Rep"},{"key":"2024061318201068600_JCS219774C2","doi-asserted-by":"publisher","first-page":"3403","DOI":"10.1242\/jcs.050526","article-title":"Axonal targeting of Caspr2 in hippocampal neurons via selective somatodendritic endocytosis","volume":"122","author":"Bel","year":"2009","journal-title":"J. Cell Sci."},{"key":"2024061318201068600_JCS219774C3","doi-asserted-by":"publisher","first-page":"21769","DOI":"10.1038\/srep21769","article-title":"LGI1 acts presynaptically to regulate excitatory synaptic transmission during early postnatal development","volume":"6","author":"Boillot","year":"2016","journal-title":"Sci. Rep."},{"key":"2024061318201068600_JCS219774C4","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1016\/j.bbapap.2015.02.008","article-title":"Interaction proteomics of canonical Caspr2 (CNTNAP2) reveals the presence of two Caspr2 isoforms with overlapping interactomes","volume":"1854","author":"Chen","year":"2015","journal-title":"Biochim. Biophys. Acta"},{"key":"2024061318201068600_JCS219774C5","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1083\/jcb.135.5.1355","article-title":"Molecular composition of the node of Ranvier: identification of ankyrin-binding cell adhesion molecules neurofascin (mucin+\/third FNIII domain-) and NrCAM at nodal axon segments","volume":"135","author":"Davis","year":"1996","journal-title":"J. Cell Biol."},{"key":"2024061318201068600_JCS219774C6","doi-asserted-by":"publisher","first-page":"e1006376","DOI":"10.1371\/journal.pgen.1006376","article-title":"Secretion-positive LGI1 mutations linked to lateral temporal epilepsy impair binding to ADAM22 and ADAM23 receptors","volume":"12","author":"Dazzo","year":"2016","journal-title":"PLoS Genet."},{"key":"2024061318201068600_JCS219774C7","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1186\/1741-7007-9-66","article-title":"Characterization of the axon initial segment (AIS) of motor neurons and identification of a para-AIS and a juxtapara-AIS, organized by protein 4.1B","volume":"9","author":"Duflocq","year":"2011","journal-title":"BMC Biol."},{"key":"2024061318201068600_JCS219774C8","doi-asserted-by":"publisher","first-page":"4695","DOI":"10.1091\/mbc.e04-03-0171","article-title":"NrCAM coupling to the cytoskeleton depends on multiple protein domains and partitioning into lipid rafts","volume":"15","author":"Falk","year":"2004","journal-title":"Mol. Biol. Cell"},{"key":"2024061318201068600_JCS219774C9","doi-asserted-by":"publisher","first-page":"1792","DOI":"10.1126\/science.1129947","article-title":"Epilepsy-related ligand\/receptor complex LGI1 and ADAM22 regulate synaptic transmission","volume":"313","author":"Fukata","year":"2006","journal-title":"Science"},{"key":"2024061318201068600_JCS219774C10","doi-asserted-by":"publisher","first-page":"3799","DOI":"10.1073\/pnas.0914537107","article-title":"Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy","volume":"107","author":"Fukata","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024061318201068600_JCS219774C11","doi-asserted-by":"publisher","first-page":"e11931","DOI":"10.1371\/journal.pone.0011931","article-title":"Dynamics of Kv1 channel transport in axons","volume":"5","author":"Gu","year":"2010","journal-title":"PLoS ONE"},{"key":"2024061318201068600_JCS219774C12","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1002\/ana.10280","article-title":"LGI1 is mutated in familial temporal lobe epilepsy characterized by aphasic seizures","volume":"52","author":"Gu","year":"2002","journal-title":"Ann. Neurol."},{"key":"2024061318201068600_JCS219774C13","doi-asserted-by":"publisher","first-page":"2920","DOI":"10.1073\/pnas.0511197103","article-title":"Voltage-gated ion channels in the axon initial segment of human cortical pyramidal cells and their relationship with chandelier cells","volume":"103","author":"Inda","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024061318201068600_JCS219774C14","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1097\/WCO.0b013e3283446f05","article-title":"Autoimmune epilepsies","volume":"24","author":"Irani","year":"2010","journal-title":"Curr. Opin. Neurol."},{"key":"2024061318201068600_JCS219774C15","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/ng832","article-title":"Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features","volume":"30","author":"Kalachikov","year":"2002","journal-title":"Nat. Genet."},{"key":"2024061318201068600_JCS219774C16","first-page":"167","article-title":"LGI proteins in the nervous system","volume":"5","author":"Kegel","year":"2012","journal-title":"ASN Neuro"},{"key":"2024061318201068600_JCS219774C17","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.neuron.2012.01.007","article-title":"Signal processing in the axon initial segment","volume":"73","author":"Kole","year":"2012","journal-title":"Neuron"},{"key":"2024061318201068600_JCS219774C18","doi-asserted-by":"publisher","first-page":"11433","DOI":"10.1523\/JNEUROSCI.1346-15.2015","article-title":"Selective loss of presynaptic potassium channel clusters at the cerebellar basket cell terminal pinceau in adam11 mutants reveals their role in ephaptic control of purkinje cell firing","volume":"35","author":"Kole","year":"2015","journal-title":"J. Neurosci."},{"key":"2024061318201068600_JCS219774C19","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1016\/S1474-4422(10)70137-X","article-title":"Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series","volume":"9","author":"Lai","year":"2010","journal-title":"Lancet Neurol."},{"key":"2024061318201068600_JCS219774C20","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1002\/ana.22297","article-title":"Investigations of caspr2, an autoantigen of encephalitis and neuromyotonia","volume":"69","author":"Lancaster","year":"2011","journal-title":"Ann. Neurol."},{"key":"2024061318201068600_JCS219774C21","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/S1937-6448(08)01607-9","article-title":"Compartmentalizing the neuronal plasma membrane from axon initial segments to synapses","volume":"272","author":"Lasiecka","year":"2009","journal-title":"Int. Rev. Cell Mol. Biol."},{"key":"2024061318201068600_JCS219774C22","doi-asserted-by":"publisher","first-page":"E4129","DOI":"10.1073\/pnas.1511910112","article-title":"The LGI1-ADAM22 protein complex directs synapse maturation through regulation of PSD-95 function","volume":"112","author":"Lovero","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024061318201068600_JCS219774C23","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1093\/hmg\/11.9.1119","article-title":"Mutations in the LGI1\/Epitempin gene on 10q24 cause autosomal dominant lateral temporal epilepsy","volume":"11","author":"Morante-Redolat","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2024061318201068600_JCS219774C24","doi-asserted-by":"publisher","first-page":"e46","DOI":"10.1212\/NXG.0000000000000046","article-title":"Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy","volume":"2","author":"Muona","year":"2016","journal-title":"Neurol Genet"},{"key":"2024061318201068600_JCS219774C25","doi-asserted-by":"publisher","first-page":"5731","DOI":"10.1523\/JNEUROSCI.4431-07.2008","article-title":"Postsynaptic density-93 clusters Kv1 channels at axon initial segments independently of Caspr2","volume":"28","author":"Ogawa","year":"2008","journal-title":"J. Neurosci."},{"key":"2024061318201068600_JCS219774C26","doi-asserted-by":"publisher","first-page":"1038","DOI":"10.1523\/JNEUROSCI.4661-09.2010","article-title":"ADAM22, a Kv1 channel-interacting protein, recruits membrane-associated guanylate kinases to juxtaparanodes of myelinated axons","volume":"30","author":"Ogawa","year":"2010","journal-title":"J. Neurosci."},{"key":"2024061318201068600_JCS219774C27","doi-asserted-by":"publisher","first-page":"18161","DOI":"10.1523\/JNEUROSCI.3506-13.2013","article-title":"Autoantibodies to epilepsy-related LGI1 in limbic encephalitis neutralize LGI1-ADAM22 interaction and reduce synaptic AMPA receptors","volume":"33","author":"Ohkawa","year":"2013","journal-title":"J. Neurosci."},{"key":"2024061318201068600_JCS219774C28","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1016\/j.mcn.2009.09.008","article-title":"LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology","volume":"42","author":"Owuor","year":"2009","journal-title":"Mol. Cell. Neurosci."},{"key":"2024061318201068600_JCS219774C29","doi-asserted-by":"publisher","first-page":"4135","DOI":"10.1523\/JNEUROSCI.3779-13.2014","article-title":"Selective microtubule-based transport of dendritic membrane proteins arises in concert with axon specification","volume":"34","author":"Petersen","year":"2014","journal-title":"J. Neurosci."},{"key":"2024061318201068600_JCS219774C30","doi-asserted-by":"publisher","first-page":"265","DOI":"10.3389\/fncel.2015.00265","article-title":"Inhibitory axons are targeted in hippocampal cell culture by anti-Caspr2 autoantibodies associated with limbic encephalitis","volume":"9","author":"Pinatel","year":"2015","journal-title":"Front. Cell Neurosci."},{"key":"2024061318201068600_JCS219774C31","doi-asserted-by":"publisher","first-page":"2209","DOI":"10.1242\/jcs.202267","article-title":"The Kv1-associated molecules TAG-1 and Caspr2 are selectively targeted to the axon initial segment in hippocampal neurons","volume":"130","author":"Pinatel","year":"2017","journal-title":"J. Cell Sci."},{"key":"2024061318201068600_JCS219774C32","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1083\/jcb.200305018","article-title":"Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1","volume":"162","author":"Poliak","year":"2003","journal-title":"J. Cell Biol."},{"key":"2024061318201068600_JCS219774C33","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1038\/nrn2852","article-title":"The axon initial segment and the maintenance of neuronal polarity","volume":"11","author":"Rasband","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"2024061318201068600_JCS219774C34","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1111\/j.1460-9568.2006.05277.x","article-title":"The role of Kif5B in axonal localization of Kv1 K(+) channels","volume":"25","author":"Rivera","year":"2007","journal-title":"Eur. J. Neurosci."},{"key":"2024061318201068600_JCS219774C35","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/ejhg.2013.100","article-title":"Shining a light on CNTNAP2: complex functions to complex disorders","volume":"22","author":"Rodenas-Cuadrado","year":"2014","journal-title":"Eur. J. Hum. Genet."},{"key":"2024061318201068600_JCS219774C36","doi-asserted-by":"publisher","first-page":"387","DOI":"10.7150\/ijbs.4.387","article-title":"LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11","volume":"4","author":"Sagane","year":"2008","journal-title":"Int. J. Biol. Sci."},{"key":"2024061318201068600_JCS219774C37","doi-asserted-by":"publisher","first-page":"e48557","DOI":"10.1371\/journal.pone.0048557","article-title":"Developmental expression of Kv potassium channels at the axon initial segment of cultured hippocampal neurons","volume":"7","author":"S\u00e1nchez-Ponce","year":"2012","journal-title":"PLoS ONE"},{"key":"2024061318201068600_JCS219774C38","doi-asserted-by":"publisher","first-page":"7719","DOI":"10.1073\/pnas.1618656114","article-title":"LGI1 tunes intrinsic excitability by regulating the density of axonal Kv1 channels","volume":"114","author":"Seagar","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2024061318201068600_JCS219774C39","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1002\/mgg3.215","article-title":"Identification of genetic variants of LGI1 and RTN4R (NgR1) linked to schizophrenia that are defective in NgR1-LGI1 signaling","volume":"4","author":"Thomas","year":"2016","journal-title":"Mol. Genet. Genomic Med."},{"key":"2024061318201068600_JCS219774C40","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.1083\/jcb.200305078","article-title":"Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers","volume":"162","author":"Traka","year":"2003","journal-title":"J. Cell Biol."},{"key":"2024061318201068600_JCS219774C41","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1111\/epi.12032","article-title":"Trafficking mechanisms underlying neuronal voltage-gated ion channel localization at the axon initial segment","volume":"9","author":"Vacher","year":"2012","journal-title":"Epilepsia"},{"key":"2024061318201068600_JCS219774C42","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1083\/jcb.201007113","article-title":"Cdk-mediated phosphorylation of the Kvbeta2 auxiliary subunit regulates Kv1 channel axonal targeting","volume":"192","author":"Vacher","year":"2011","journal-title":"J. Cell Biol."},{"key":"2024061318201068600_JCS219774C43","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1038\/s41467-018-03947-w","article-title":"Structural basis of epilepsy-related ligand-receptor complex LGI1-ADAM22","volume":"9","author":"Yamagata","year":"2018","journal-title":"Nat. Commun."},{"key":"2024061318201068600_JCS219774C44","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1038\/nm.3759","article-title":"Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy","volume":"21","author":"Yokoi","year":"2015","journal-title":"Nat. Med."},{"key":"2024061318201068600_JCS219774C45","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1016\/j.conb.2016.05.001","article-title":"Cytoskeletal control of axon domain assembly and function","volume":"39","author":"Zhang","year":"2016","journal-title":"Curr. Opin. Neurobiol."}],"container-title":["Journal of Cell Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1242\/jcs.219774","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.219774\/3506691\/jcs219774.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.219774\/2059158\/jcs_219774v1.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/jcs\/article-pdf\/doi\/10.1242\/jcs.219774\/3506691\/jcs219774.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,13]],"date-time":"2024-06-13T15:03:11Z","timestamp":1718290991000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/jcs\/article\/132\/2\/jcs219774\/57255\/ADAM22-and-ADAM23-modulate-the-targeting-of-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,15]]},"references-count":45,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,1,15]]}},"URL":"https:\/\/doi.org\/10.1242\/jcs.219774","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/311365","asserted-by":"object"}]},"ISSN":["1477-9137","0021-9533"],"issn-type":[{"value":"1477-9137","type":"electronic"},{"value":"0021-9533","type":"print"}],"subject":[],"published":{"date-parts":[[2019,1,15]]},"article-number":"jcs219774"}}