title: NMDA receptor modulation by the neuropeptide apelin: implications for excitotoxic injury.
abstract: Excitotoxic neuronal damage via over-activation of the NMDA receptor has been implicated in many neurodegenerative diseases. In vitro modeling of excitotoxic injury has shown that activation of G-protein coupled receptors (GPCRs) counteracts such injury through modulation of neuronal pro-survival 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-survival signaling as well as inhibiting NMDA receptor-mediated excitotoxic signaling cascades. Our results demonstrate that (i) apelin activates pro-survival signaling via inositol trisphosphate (IP(3) ), protein kinase C (PKC), mitogen-activated protein kinase kinase 1/2 (MEK1/2), and extracellular signal-regulated kinase-1/2 (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-mediated injury to protect neurons against excitotoxicity. Defining apelin-mediated neuroprotection advances our understanding of neuroprotective pathways and will potentially improve our ability to develop therapeutics for excitotoxicity-associated neurodegenerative disorders.
authors.affiliation: Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Denise R
authors.initials: DR
authors.lastname: Cook
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Gleichman
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Cross
authors.forename: Shachee
authors.initials: S
authors.lastname: Doshi
authors.forename: Wenzhe
authors.initials: W
authors.lastname: Ho
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Jordan-Sciutto
authors.forename: David R
authors.initials: DR
authors.lastname: Lynch
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Kolson
mesh_terms: D000818:Animals; D000073861:Apelin; D015153:Blotting, Western; D001921:Brain / Q000166:cytology; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D055724:Electrophysiological Phenomena; D015658:HIV Infections / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents; D009498:Neurotoxins / Q000633:toxicity*; D018408:Patch-Clamp Techniques; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: C115436:APLN protein, human; D000073861:Apelin; D036341:Intercellular Signaling Peptides and Proteins; D007473:Ion Channels; C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D009498:Neurotoxins; D016194:Receptors, N-Methyl-D-Aspartate; D002154:Calpain; D002118:Calcium