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In a young man with migraine with aura including hemiplegia, we identified a novel <jats:italic>SLC1A3<\/jats:italic> mutation that predicts the substitution of a conserved threonine by proline at position 387 (T387P) in <jats:italic>h<\/jats:italic>EAAT1. To evaluate the functional effects of the novel variant, we expressed the wildtype or mutant <jats:italic>h<\/jats:italic>EAAT1 in mammalian cells and performed whole-cell patch clamp, fast substrate application, and biochemical analyses. T387P diminishes <jats:italic>h<\/jats:italic>EAAT1 glutamate uptake rates and reduces the number of <jats:italic>h<\/jats:italic>EAAT1 in the surface membrane. Whereas <jats:italic>h<\/jats:italic>EAAT1 anion currents display normal ligand and voltage dependence in cells internally dialyzed with Na<jats:sup>+<\/jats:sup>-based solution, no anion currents were observed with internal K<jats:sup>+<\/jats:sup>. Fast substrate application demonstrated that T387P abolishes K<jats:sup>+<\/jats:sup>-bound retranslocation. Our finding expands the phenotypic spectrum of genetic variation in <jats:italic>SLC1A3<\/jats:italic> and highlights impaired K<jats:sup>+<\/jats:sup> binding to <jats:italic>h<\/jats:italic>EAAT1 as a novel mechanism of glutamate transport dysfunction in human disease.<\/jats:p>","DOI":"10.1038\/s41598-017-14176-4","type":"journal-article","created":{"date-parts":[[2017,10,18]],"date-time":"2017-10-18T11:10:18Z","timestamp":1508325018000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Impaired K+ binding to glial glutamate transporter EAAT1 in migraine"],"prefix":"10.1038","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5296-4918","authenticated-orcid":false,"given":"Peter","family":"Kovermann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"Hessel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9098-3466","authenticated-orcid":false,"given":"Daniel","family":"Kortzak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2319-7032","authenticated-orcid":false,"given":"Joanna C.","family":"Jen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes","family":"Koch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8602-9952","authenticated-orcid":false,"given":"Christoph","family":"Fahlke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Freilinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,10,24]]},"reference":[{"key":"14176_CR1","doi-asserted-by":"publisher","first-page":"165","DOI":"10.3389\/fendo.2013.00165","volume":"4","author":"Y Zhou","year":"2013","unstructured":"Zhou, Y. & Danbolt, N. 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