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Here, an activity\u2010regulated, high\u2010affinity Gln transport system is described in developing and mature neuron\u2010enriched hippocampal cultures that is potently inhibited by riluzole (<jats:styled-content style=\"fixed-case\">IC<\/jats:styled-content><jats:sub>50<\/jats:sub>1.3\u00a0\u00b1\u00a00.5\u00a0\u03bcM), an anti\u2010glutamatergic drug, and is blocked by low concentrations of 2\u2010(methylamino)isobutyrate (Me<jats:styled-content style=\"fixed-case\">AIB<\/jats:styled-content>), a system A transport inhibitor. K<jats:sup>+<\/jats:sup>\u2010stimulated Me<jats:styled-content style=\"fixed-case\">AIB<\/jats:styled-content>transport displays an affinity (<jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub>) for Me<jats:styled-content style=\"fixed-case\">AIB<\/jats:styled-content>of 37\u00a0\u00b1\u00a01.2\u00a0\u03bcM, saturates at ~\u00a0200\u00a0\u03bcM, is dependent on extracellular Ca<jats:sup>2+<\/jats:sup>, and is blocked by inhibition of voltage\u2010gated Ca<jats:sup>2+<\/jats:sup>channels. Spontaneous Me<jats:styled-content style=\"fixed-case\">AIB<\/jats:styled-content>transport is also dependent on extracellullar Ca<jats:sup>2+<\/jats:sup>and voltage\u2010gated calcium channels, but is also blocked by the Na<jats:sup>+<\/jats:sup>channel blocker tetrodotoxin, by Glu receptor antagonists, and by<jats:styled-content style=\"fixed-case\">GABA<\/jats:styled-content>indicating its dependence on intact neural circuits driven by endogenous glutamatergic activity. The transport of Me<jats:styled-content style=\"fixed-case\">AIB<\/jats:styled-content>itself does not rely on Ca<jats:sup>2+<\/jats:sup>, but on Na<jats:sup>+<\/jats:sup>ions, and is<jats:styled-content style=\"fixed-case\">pH<\/jats:styled-content>sensitive. Activity\u2010regulated, riluzole\u2010sensitive spontaneous and K<jats:sup>+<\/jats:sup>\u2010stimulated transport is minimal at 7\u20138\u00a0days<jats:italic>in\u00a0vitro<\/jats:italic>, coordinately induced during the next 2\u00a0weeks and is maximally expressed by days<jats:italic>in\u00a0vitro<\/jats:italic>&gt;\u00a020; the known period for maturation of the Glu\/Gln cycle and regulated pre\u2010synaptic Glu release. Competition analyses with various amino acids indicate that Gln is the most likely physiological substrate. Activity\u2010regulated Gln\/Me<jats:styled-content style=\"fixed-case\">AIB<\/jats:styled-content>transport is not observed in astrocytes. The functional identification of activity\u2010regulated, high\u2010affinity, riluzole\u2010sensitive Gln\/Me<jats:styled-content style=\"fixed-case\">AIB<\/jats:styled-content>transport in hippocampal neurons may have important ramifications in the neurobiology of activity\u2010stimulated pre\u2010synaptic Glu release, the Glu\/Gln cycle between astrocytes and neurons, and neuronal Glu\u2010induced excitotoxicity.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc14046-fig-0009-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><jats:p><jats:bold>Cover Image<\/jats:bold>for this issue: doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1111\/jnc.13805\">10.1111\/jnc.13805<\/jats:ext-link>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14046","type":"journal-article","created":{"date-parts":[[2017,4,19]],"date-time":"2017-04-19T18:43:03Z","timestamp":1492627383000},"page":"29-40","source":"Crossref","is-referenced-by-count":23,"title":["Functional identification of activity\u2010regulated, high\u2010affinity glutamine transport in hippocampal neurons inhibited by riluzole"],"prefix":"10.1111","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4598-9898","authenticated-orcid":false,"given":"Jeffrey D.","family":"Erickson","sequence":"first","affiliation":[{"name":"Neuroscience Center of Excellence School of Medicine Lousiania State University Health New Orleans New Orleans Louisiana USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,5,18]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2741\/2067"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110942200"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1179\/016164107X159225"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00665.2001"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3940(00)01536-6"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00370302"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1984.tb05396.x"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1466-13.2013"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1177\/088307389701200802"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2009.09.015"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M200374200"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7569903"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.490350513"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.23-23-08212.2003"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M608548200"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200201070"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(92)90597-Z"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jcbfm.9600490"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1990.70.1.43"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13311-014-0305-y"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2005.11.016"},{"key":"e_1_2_8_23_1","doi-asserted-by":"crossref","first-page":"7121","DOI":"10.1523\/JNEUROSCI.5221-04.2005","article-title":"Homeostatic scaling of vesicular glutamate and GABA transporter expression in rat neocortical circuits","volume":"25","author":"Gois S.","year":"2005","journal-title":"J. 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