GluN2A-NMDA receptor-mediated sustained Ca2+ influx leads to homocysteine-induced neuronal cell death
GluN2A-NMDA receptor-mediated sustained Ca2+ influx leads to homocysteine-induced neuronal cell death
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DOI：
10.1074/jbc.ra119.008820
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发表时间：
2019-07-19
影响因子：
4.8
通讯作者：
Poddar, Ranjana
中科院分区：
文献类型：
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作者：
Deep, Satya Narayan;Mitra, Sumonto;Poddar, Ranjana
同型半胱氨酸是甲硫氨酸循环的一种代谢产物，是N -甲基 - D -天冬氨酸受体（NMDAR，一种谷氨酸受体亚型）的已知激动剂，并参与NMDAR介导的神经毒性。我们先前的研究结果表明，细胞外信号调节激酶/丝裂原活化蛋白激酶（ERK MAPK）的磷酸化和激活持续增加促进了同型半胱氨酸诱导的、NMDAR介导的神经毒性。在当前的研究中，我们研究了含GluN1/GluN2A的功能性NMDAR（GluN2A - NMDAR）和含GluN1/GluN2B的功能性NMDAR（GluN2B - NMDAR）在同型半胱氨酸诱导的神经毒性中的作用。我们的研究结果显示，将原代皮质神经元培养物暴露于同型半胱氨酸会导致细胞内Ca²⁺持续低水平升高。我们还表明，对GluN2A - NMDAR进行药理抑制或GluN2A亚基的基因缺失会减弱同型半胱氨酸诱导的细胞内Ca²⁺升高。我们的结果进一步确定了GluN2A - NMDAR在同型半胱氨酸介导的ERK MAPK持续磷酸化和神经元细胞死亡中的作用。值得注意的是，GluN2A - NMDAR在同型半胱氨酸诱导的神经毒性中的优先作用与谷氨酸 - NMDAR诱导的兴奋性毒性细胞死亡明显不同，后者涉及GluN2B - NMDAR的过度激活且与ERK MAPK激活无关。这些发现表明GluN2A - NMDAR介导的信号传导在同型半胱氨酸诱导的神经毒性中起关键作用。
Homocysteine, a metabolite of the methionine cycle, is a known agonist of N-methyl-d-aspartate receptor (NMDAR), a glutamate receptor subtype and is involved in NMDAR-mediated neurotoxicity. Our previous findings have shown that homocysteine-induced, NMDAR-mediated neurotoxicity is facilitated by a sustained increase in phosphorylation and activation of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK MAPK). In the current study, we investigated the role GluN1/GluN2A-containing functional NMDAR (GluN2A-NMDAR) and GluN1/GluN2B-containing functional NMDAR (GluN2B-NMDAR) in homocysteine-induced neurotoxicity. Our findings revealed that exposing primary cortical neuronal cultures to homocysteine leads to a sustained low-level increase in intracellular Ca2+. We also showed that pharmacological inhibition of GluN2A-NMDAR or genetic deletion of the GluN2A subunit attenuates homocysteine-induced increase in intracellular Ca2+. Our results further established the role of GluN2A-NMDAR in homocysteine-mediated sustained ERK MAPK phosphorylation and neuronal cell death. Of note, the preferential role of GluN2A-NMDAR in homocysteine-induced neurotoxicity was distinctly different from glutamate-NMDAR-induced excitotoxic cell death that involves overactivation of GluN2B-NMDAR and is independent of ERK MAPK activation. These findings indicate a critical role of GluN2A-NMDAR-mediated signaling in homocysteine-induced neurotoxicity.