{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T02:28:17Z","timestamp":1780108097449,"version":"3.54.0"},"reference-count":51,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,2,17]],"date-time":"2009-02-17T00:00:00Z","timestamp":1234828800000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2009,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>The deleterious effects of glutamate excitotoxicity are well described for central nervous system gray matter. Although overactivation of glutamate receptors also contributes to axonal injury, the mechanisms are poorly understood. Our goal was to elucidate the mechanisms of kainate receptor\u2013dependent axonal Ca<jats:sup>2+<\/jats:sup>deregulation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Dorsal column axons were loaded with a Ca<jats:sup>2+<\/jats:sup>indicator and imaged in vitro using confocal laser\u2010scanning microscopy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Activation of glutamate receptor 6 (GluR6) kainate receptors promoted a substantial increase in axonal [Ca<jats:sup>2+<\/jats:sup>]. This Ca<jats:sup>2+<\/jats:sup>accumulation was due not only to influx from the extracellular space, but a significant component originated from ryanodine\u2010dependent intracellular stores, which, in turn, depended on activation of L\u2010type Ca<jats:sup>2+<\/jats:sup>channels: ryanodine, nimodipine, or nifedipine blocked the agonist\u2010induced Ca<jats:sup>2+<\/jats:sup>increase. Also, GluR6 stimulation induced intraaxonal production of nitric oxide (NO), which greatly enhanced the Ca<jats:sup>2+<\/jats:sup>response: quenching of NO with intraaxonal (but not extracellular) scavengers, or inhibition of neuronal NO synthase with intraaxonal N\u03c9\u2010nitro\u2010L\u2010arginine methyl ester, blocked the Ca<jats:sup>2+<\/jats:sup>increase. Loading axons with a peptide that mimics the C\u2010terminal PDZ binding sequence of GluR6, thus interfering with the coupling of GluR6 to downstream effectors, greatly reduced the agonist\u2010induced axonal Ca<jats:sup>2+<\/jats:sup>increase. Immunohistochemistry showed GluR6\/7 clusters on the axolemma colocalized with neuronal NO synthase and Ca<jats:sub>v<\/jats:sub>1.2.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Myelinated spinal axons express functional GluR6\u2010containing kainate receptors, forming part of novel signaling complexes reminiscent of postsynaptic membranes of glutamatergic synapses. The ability of such axonal \u201cnanocomplexes\u201d to release toxic amounts of Ca<jats:sup>2+<\/jats:sup>may represent a key mechanism of axonal degeneration in disorders such as multiple sclerosis where abnormal accumulation of glutamate and NO are known to occur. Ann Neurol 2009<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.21533","type":"journal-article","created":{"date-parts":[[2009,2,17]],"date-time":"2009-02-17T15:06:46Z","timestamp":1234883206000},"page":"151-159","source":"Crossref","is-referenced-by-count":90,"title":["Glutamate receptors on myelinated spinal cord axons: I. GluR6 kainate receptors"],"prefix":"10.1002","volume":"65","author":[{"given":"Mohamed","family":"Ouardouz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Coderre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajoy","family":"Basak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald W.","family":"Zamponi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shameed","family":"Hameed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata","family":"Rehak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinghua","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"Trapp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter K.","family":"Stys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,2,17]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199403033300907"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.12-02-00430.1992"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1995.74.1.369"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1089\/neu.1997.14.299"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2005.03.031"},{"key":"e_1_2_6_7_2","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1523\/JNEUROSCI.17-03-01055.1997","article-title":"Role of NMDA and non\u2010NMDA ionotropic glutamate receptors in traumatic spinal cord axonal injury","volume":"17","author":"Agrawal SK","year":"1997","journal-title":"J Neurosci"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-14-j0002.1999"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.116798"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-12-04237.2001"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600455"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.STR.31.8.1945"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.14-11-06598.1994"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/71555"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/71548"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0398-291"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-03-01190.2000"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20221"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.17.10229"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2003.08.004"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20275"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04302"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04301"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04474"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.16-01-00200.1996"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7580.2007.00733.x"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1097\/00004647-200209000-00006"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/0922-4106(94)90024-8"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0123-06.2005"},{"key":"e_1_2_6_30_2","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S0022-3565(24)37464-6","article-title":"The methylglutamate, SYM 2081, is a potent and highly selective agonist at kainate receptors","volume":"285","author":"Donevan SD","year":"1998","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2003.08.016"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(03)00436-7"},{"key":"e_1_2_6_33_2","doi-asserted-by":"crossref","first-page":"8641","DOI":"10.1523\/JNEUROSCI.23-25-08641.2003","article-title":"A role for extracellular Na+ in the channel gating of native and recombinant kainate receptors","volume":"23","author":"Paternain AV","year":"2003","journal-title":"J Neurosci"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5542-06.2007"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0166-2236(00)01746-X"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.98.2.735"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1993.tb13429.x"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-006-0265-6"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-8993(91)91154-S"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.16.8830"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1136624100"},{"key":"e_1_2_6_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1854"},{"key":"e_1_2_6_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nn1850"},{"key":"e_1_2_6_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/89506"},{"key":"e_1_2_6_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1253"},{"key":"e_1_2_6_46_2","doi-asserted-by":"publisher","DOI":"10.1007\/s002320001022"},{"key":"e_1_2_6_47_2","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00029.2006"},{"key":"e_1_2_6_48_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0019-08.2008"},{"key":"e_1_2_6_49_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072873"},{"key":"e_1_2_6_50_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M513490200"},{"key":"e_1_2_6_51_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199801293380502"},{"key":"e_1_2_6_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21539"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fana.21533","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.21533","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,7]],"date-time":"2025-02-07T19:27:13Z","timestamp":1738956433000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.21533"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2]]},"references-count":51,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2009,2]]}},"alternative-id":["10.1002\/ana.21533"],"URL":"https:\/\/doi.org\/10.1002\/ana.21533","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,2]]}}}