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Neurochem.<\/jats:italic> (2011) <jats:bold>118<\/jats:bold>, 1113\u20131123.<\/jats:p><\/jats:sec><jats:sec><jats:title>Abstract<\/jats:title><jats:p>Excitotoxic neuronal damage via over\u2010activation of the NMDA receptor has been implicated in many neurodegenerative diseases. <jats:italic>In vitro<\/jats:italic> modeling of excitotoxic injury has shown that activation of G\u2010protein coupled receptors (GPCRs) counteracts such injury through modulation of neuronal pro\u2010survival pathways and\/or NMDA receptor signaling. We have previously demonstrated that the GPCR APJ and its endogenous neuropeptide ligand apelin can protect neurons against excitotoxicity, but the mechanism(s) of this neuroprotection remain incompletely understood. We hypothesized that apelin can promote neuronal survival by activating pro\u2010survival signaling as well as inhibiting NMDA receptor\u2010mediated excitotoxic signaling cascades. Our results demonstrate that (i) apelin activates pro\u2010survival signaling via inositol trisphosphate (IP<jats:sub>3<\/jats:sub>), protein kinase C (PKC), mitogen\u2010activated protein kinase kinase 1\/2 (MEK1\/2), and extracellular signal\u2010regulated kinase\u20101\/2 (ERK1\/2) to protect against excitotoxicity, and (ii) apelin inhibits excitotoxic signaling by attenuating NMDA receptor and calpain activity, and by modulating NMDA receptor subunit NR2B phosphorylation at serine 1480. These studies delineate a novel apelinergic signaling pathway that concurrently promotes survival and limits NMDA receptor\u2010mediated injury to protect neurons against excitotoxicity. Defining apelin\u2010mediated neuroprotection advances our understanding of neuroprotective pathways and will potentially improve our ability to develop therapeutics for excitotoxicity\u2010associated neurodegenerative disorders.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1471-4159.2011.07383.x","type":"journal-article","created":{"date-parts":[[2011,7,12]],"date-time":"2011-07-12T20:57:52Z","timestamp":1310504272000},"page":"1113-1123","source":"Crossref","is-referenced-by-count":65,"title":["NMDA receptor modulation by the neuropeptide apelin: implications for excitotoxic injury"],"prefix":"10.1111","volume":"118","author":[{"given":"Denise R.","family":"Cook","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy J.","family":"Gleichman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie A.","family":"Cross","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shachee","family":"Doshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenzhe","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly L.","family":"Jordan\u2010Sciutto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Lynch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis L.","family":"Kolson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2011,8,8]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.490420510"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(00)00367-8"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2007.05.018"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.18.9407-9419.2002"},{"issue":"1","key":"e_1_2_7_6_1","first-page":"S61","article-title":"Functional expression of the seven\u2010transmembrane HIV\u20101 co\u2010receptor APJ in neural cells","volume":"6","author":"Choe W.","year":"2000","journal-title":"J. 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