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However, the mechanism underlying this alcohol\u2010induced neuronal death is not fully understood. Utilizing primary cultures of cerebellar granule neurons (\n                    <jats:styled-content style=\"fixed-case\">CGN<\/jats:styled-content>\n                    ), we tested the hypothesis that the alcohol\u2010induced increase in intracellular calcium [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    causes the death of\n                    <jats:styled-content style=\"fixed-case\">CGN<\/jats:styled-content>\n                    . Alcohol induced a dose\u2010dependent (200\u2013800\u00a0mg\/dL) neuronal death within 24\u00a0h. Ratiometric Ca\n                    <jats:sup>2+<\/jats:sup>\n                    imaging with Fura\u20102 revealed that alcohol causes a rapid (1\u20132\u00a0min), dose\u2010dependent increase in [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    , which persisted for the duration of the experiment (5 or 7\u00a0min). The alcohol\u2010induced increase in [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    was observed in Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010free media, suggesting intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release. Pre\u2010treatment of\n                    <jats:styled-content style=\"fixed-case\">CGN<\/jats:styled-content>\n                    cultures with an inhibitor (2\u2010\n                    <jats:styled-content style=\"fixed-case\">APB<\/jats:styled-content>\n                    ) of the inositol\u2010triphosphate receptor (\n                    <jats:styled-content style=\"fixed-case\">IP<\/jats:styled-content>\n                    <jats:sub>3<\/jats:sub>\n                    R), which regulates Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release from the endoplasmic reticulum (\n                    <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>\n                    ), blocked both the alcohol\u2010induced rise in [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    and the neuronal death caused by alcohol. Similarly, pre\u2010treatment with\n                    <jats:styled-content style=\"fixed-case\">BAPTA<\/jats:styled-content>\n                    \/\n                    <jats:styled-content style=\"fixed-case\">AM<\/jats:styled-content>\n                    , a Ca\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010chelator, also inhibited the alcohol\u2010induced surge in [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    and prevented neuronal death. In conclusion, alcohol disrupts [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    homeostasis in\n                    <jats:styled-content style=\"fixed-case\">CGN<\/jats:styled-content>\n                    by releasing Ca\n                    <jats:sup>2+<\/jats:sup>\n                    from intracellular stores, resulting in a sustained increase in [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    . This sustained increase in [Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ]\n                    <jats:sub>i<\/jats:sub>\n                    may be a key determinant in the mechanism underlying alcohol\u2010induced neuronal death.\n                  <\/jats:p>","DOI":"10.1111\/jnc.12076","type":"journal-article","created":{"date-parts":[[2012,11,1]],"date-time":"2012-11-01T11:11:19Z","timestamp":1351768279000},"page":"323-335","source":"Crossref","is-referenced-by-count":39,"title":["Intracellular calcium plays a critical role in the alcohol\u2010mediated death of cerebellar granule neurons"],"prefix":"10.1111","volume":"124","author":[{"given":"Dimitrios E.","family":"Kouzoukas","sequence":"first","affiliation":[{"name":"Department of Anatomy and Cell Biology Carver College of Medicine The University of Iowa Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology Carver College of Medicine The University of Iowa Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maysaam","family":"Takapoo","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology Carver College of Medicine The University of Iowa Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Moninger","sequence":"additional","affiliation":[{"name":"University of Iowa Central Microscopy Research Facilities Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramesh C.","family":"Bhalla","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology Carver College of Medicine The University of Iowa Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas J.","family":"Pantazis","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology Carver College of Medicine The University of Iowa Iowa City Iowa USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,12,6]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/27094"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420440203"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0165-3806(02)00549-7"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ntt.2003.08.004"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.76.1.514"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410923200"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1530-0277.2008.00769.x"},{"key":"e_1_2_7_9_1","first-page":"93","article-title":"Tolerance to the effects of alcohol","volume":"8","author":"Chesher G.","year":"1992","journal-title":"Alcohol Drugs Driving"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.ALC.0000056615.34253.A8"},{"key":"e_1_2_7_11_1","first-page":"87","volume-title":"Methods in Neurosciences","author":"Dutton G. 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