NMDA receptor modulation by the neuropeptide apelin: implications for excitotoxic injury.
NMDA receptor modulation by the neuropeptide apelin: implications for excitotoxic injury.
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DOI：
10.1111/j.1471-4159.2011.07383.x
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发表时间：
2011-09
影响因子：
4.7
通讯作者：
Kolson DL
中科院分区：
文献类型：
--
作者：
Cook DR;Gleichman AJ;Cross SA;Doshi S;Ho W;Jordan-Sciutto KL;Lynch DR;Kolson DL
通过过度激活NMDA受体引起的兴奋性毒性神经元损伤与许多神经退行性疾病有关。兴奋性毒性损伤的体外建模已经表明，G蛋白偶联受体（GPCR）的活化通过调节神经元促存活途径和/或NMDA受体信号传导来抵消这种损伤。我们先前已经证明GPCR APJ及其内源性神经肽配体apelin可以保护神经元免受兴奋性毒性，但这种神经保护的机制仍不完全清楚。我们假设爱帕琳可以通过激活促存活信号以及抑制NMDA受体介导的兴奋性毒性信号级联来促进神经元存活。我们的结果表明：（i）爱帕琳通过三磷酸肌醇（IP 3）、蛋白激酶C（PKC）、促分裂原活化蛋白激酶激酶1/2（MEK 1/2）和细胞外信号调节激酶1/2（ERK 1/2）激活促生存信号传导，以防止兴奋性毒性，和（ii）爱帕琳通过减弱NMDA受体和钙蛋白酶活性来抑制兴奋性毒性信号传导，以及通过调节NMDA受体亚基NR 2B在丝氨酸1480处的磷酸化。这些研究描绘了一种新的apelinergic信号通路，同时促进生存和限制NMDA受体介导的损伤，以保护神经元免受兴奋性毒性。定义apelin介导的神经保护促进了我们对神经保护途径的理解，并将潜在地提高我们开发兴奋性毒性相关神经退行性疾病治疗剂的能力。
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 (IP3), 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.
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DOI：
10.1073/pnas.96.14.8212
发表时间：
1999-07-06
影响因子：
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