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GABA modulates the actions of microglia, indicating an important role for astrocytes beyond that of influencing neurotransmitter function. Here we report on the mechanisms by which astrocytes release GABA. Astrocytes were found to express the mRNA and protein for multiple GABA transporters, and multiple receptors for glutamate, GABA, and glycine. In culture, untreated human astrocytes maintained an intracellular GABA level of 2.32 mM. They exported GABA into the culture medium so that an intracellular\u2010extracellular gradient of 3.64 fold was reached. Inhibitors of the GABA transporters GAT1, GAT2, and GAT3, significantly reduced this export in a Ca<jats:sup>2+<\/jats:sup>\u2010independent fashion. Intracellular GABA levels were enhanced by treatment with the GABA\u2010T inhibitors gabaculine or vigabatrin. Treatment with glutamate increased GABA release in a concentration\u2010dependent fashion. This was partially inhibited by blockers of <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>D<\/jats:sc>\u2010aspartate and kainate receptors. Conversely, glycine and <jats:sc>D<\/jats:sc>\u2010serine, co\u2010agonists of NMDA receptors, enhanced the GABA release. GABA release was accompanied by an increase in intracellular Ca<jats:sup>2+<\/jats:sup> concentration ([Ca<jats:sup>2+<\/jats:sup>]<jats:sub>i<\/jats:sub>) and was reduced by adding the Ca<jats:sup>2+<\/jats:sup> chelator, BAPTA\u2010AM to the medium. These data indicate that astrocytes continuously synthesize GABA and that there are multiple mechanisms which can mediate its release. Each of these may play a role in the physiological functioning of astrocytes. \u00a9 2011 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/glia.21202","type":"journal-article","created":{"date-parts":[[2011,7,11]],"date-time":"2011-07-11T17:24:29Z","timestamp":1310405069000},"page":"1600-1611","source":"Crossref","is-referenced-by-count":105,"title":["Mechanisms of GABA release from human astrocytes"],"prefix":"10.1002","volume":"59","author":[{"given":"Moonhee","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edith G.","family":"McGeer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick 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