Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses.
Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses.
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内在的抗氧化防御对神经元的寿命很重要。我们发现，突触活动，通过NMDA受体（NMDAR）信号传导，通过改变硫氧还蛋白-过氧化物酶系统增强抗氧化防御。突触活性增强硫氧还蛋白活性，促进过氧化的过氧化物酶的还原，并促进对氧化应激的抵抗。耐药性是由协调的转录变化介导的：突触NMDAR活性使一种新的FOXO靶基因硫氧还蛋白抑制剂Txnip失活。相反，NMDAR阻断在体内和体外上调Txnip，其中它结合硫氧还蛋白并促进对氧化损伤的脆弱性。突触活动还分别通过C/EBPβ和AP-1上调过氧化物酶再激活基因Sestrin 2和Sulfiredoxin。模仿这些表达变化足以加强抗氧化防御。突触NMDAR的跨突触刺激对于增强抗氧化防御至关重要：所有（突触和突触外）NMDAR的慢性浴激活不诱导抗氧化作用。因此，突触NMDAR活性可能影响与氧化损伤相关的病理过程的进展。
Intrinsic antioxidant defences are important for neuronal longevity. We show that synaptic activity, acting via NMDA receptor (NMDAR) signaling, boosts antioxidant defences through changes to the thioredoxin-peroxiredoxin system. Synaptic activity enhances thioredoxin activity, facilitates the reduction of overoxidized peroxiredoxins, and promotes resistance to oxidative stress. Resistance is mediated by coordinated transcriptional changes: synaptic NMDAR activity inactivates a novel FOXO target gene, the thioredoxin inhibitor Txnip. Conversely, NMDAR blockade upregulates Txnip in vivo and in vitro, where it binds thioredoxin and promotes vulnerability to oxidative damage. Synaptic activity also up-regulates the peroxiredoxin re-activating genes Sestrin2 and Sulfiredoxin, via C/EBPβ and AP-1 respectively. Mimicking these expression changes is sufficient to strengthen antioxidant defences. Trans-synaptic stimulation of synaptic NMDARs is crucial for boosting antioxidant defences: chronic bath activation of all (synaptic and extrasynaptic) NMDARs induces no antioxidative effects. Thus, synaptic NMDAR activity may influence the progression of pathological processes associated with oxidative damage.