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Na<jats:sub>x<\/jats:sub> is known to interact directly with Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010<jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase, leading to lactate production in the brain. To investigate the role of Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010<jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase in peripheral nerve regeneration, in this study, we applied ouabain, a Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010<jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase inhibitor, to the cut site for 4\u00a0weeks with an osmotic pump. While functional recovery and nerve reinnervation to the toe started at 5\u00a0weeks after axotomy and were completed by 7\u00a0weeks, ouabain delayed them by 2\u00a0weeks. The delay by ouabain was improved by lactate, and its effect was blocked by \u03b1\u2010cyano\u20104\u2010hydroxy\u2010cinnamic acid (<jats:styled-content style=\"fixed-case\">CIN<\/jats:styled-content>), a broad monocarboxylate transporter (<jats:styled-content style=\"fixed-case\">MCT<\/jats:styled-content>) inhibitor. In primary cultures of dorsal root ganglia, neurite outgrowth of neurons and lactate release into the culture medium was inhibited by ouabain. Conversely, lactate enhanced the neurite outgrowth, which was blocked by <jats:styled-content style=\"fixed-case\">CIN<\/jats:styled-content>, but not by <jats:styled-content style=\"fixed-case\">AR<\/jats:styled-content>\u2010C155858, a <jats:styled-content style=\"fixed-case\">MCT<\/jats:styled-content>1\/2\u2010selective inhibitor. <jats:styled-content style=\"fixed-case\">ET<\/jats:styled-content>\u20101 and <jats:styled-content style=\"fixed-case\">ET<\/jats:styled-content>\u20103 increased neurite outgrowth of neurons, which was attenuated by an <jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub>R<\/jats:styled-content> antagonist, ouabain and 2 protein kinase C inhibitors. Taken together with the finding that <jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub>R<\/jats:styled-content> was expressed in Schwann cells, these results demonstrate that <jats:styled-content style=\"fixed-case\">ET<\/jats:styled-content> enhanced neurite outgrowth of neurons mediated by Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010<jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase via <jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub>R<\/jats:styled-content> in Schwann cells. This study suggests that Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\u2010<jats:styled-content style=\"fixed-case\">ATP<\/jats:styled-content>ase coupled to the <jats:styled-content style=\"fixed-case\">ET<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub>R<\/jats:styled-content> system plays a critical role in peripheral nerve regeneration via lactate signalling.<\/jats:p>","DOI":"10.1111\/ejn.13647","type":"journal-article","created":{"date-parts":[[2017,7,12]],"date-time":"2017-07-12T14:35:11Z","timestamp":1499870111000},"page":"2096-2107","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Na<sup>+<\/sup>\/K<sup>+<\/sup>\u2010<scp>ATP<\/scp>ase coupled to endothelin receptor type B stimulates peripheral nerve regeneration via lactate signalling"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7801-6609","authenticated-orcid":false,"given":"Nguyen H.","family":"Tu","sequence":"first","affiliation":[{"name":"Department of Medical Chemistry Kansai Medical University 2\u20105\u20101 Shin\u2010machi Hirakata 573\u20101010 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tayo","family":"Katano","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry Kansai Medical University 2\u20105\u20101 Shin\u2010machi Hirakata 573\u20101010 Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1469-5347","authenticated-orcid":false,"given":"Shinji","family":"Matsumura","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry Kansai Medical University 2\u20105\u20101 Shin\u2010machi Hirakata 573\u20101010 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