The Journal of Membrane Biology ( IF 2.3 ) Pub Date : 2021-07-29 , DOI: 10.1007/s00232-021-00196-9 E M Kawamoto 1 , M M Cararo-Lopes 2 , P F Kinoshita 2 , L E M Quintas 3 , L S Lima 2 , D Z Andreotti 1, 2 , C Scavone 2
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Amyloid-β peptide (Aβ) has been shown to cause synaptic dysfunction and can render neurons vulnerable to excitotoxicity and oxidative stress. Na,K-ATPase plays an important role to maintain cell ionic equilibrium and it can be modulated by N-methyl-d-aspartate (NMDA)–nitric oxide (NO)–cyclic GMP pathway. Disruption of NO synthase (NOS) activity and reactive oxygen species (ROS) production could lead to changes in Na,K-ATPase isoforms’ activities that may be detrimental to the cells. Our aim was to evaluate the signaling pathways of Aβ in relation to NMDA–NOS–cyclic GMP versus oxidative stress on α1-/α2,3-Na,K-ATPase activities in rat hippocampal slices. Aβ1–40 induced a concentration-dependent increase of NOS activity and increased cyclic guanosine monophosphate (cGMP), TBARS (thiobarbituric acid reactive substances), and 3-Nitrotyrosine (3-NT)-modified protein levels in rat hippocampal slices. The increase in NOS activity and cyclic GMP levels induced by Aβ1–40 was completely blocked by MK-801 (inhibitor of NMDA receptor) and L-NAME (inhibitor of NOS) pre-treatment but changes in TBARS levels were only partially blocked by both compounds. The Aβ treatment also decreased Na,K-ATPase activity which was reverted by N-nitro-l-arginine methyl ester hydrochloride (L-NAME) but not by MK-801 pre-treatment. The decrease in enzyme activity induced by Aβ was isoform-specific since only α1-Na,K-ATPase was affected. These findings suggest that the activation of NMDA–NOS signaling cascade linked to α2,3-Na,K-ATPase activity may mediate an adaptive, neuroprotective response to Aβ in rat hippocampus.
Graphic Abstract
中文翻译：
一氧化氮-环状 GMP 和氧化应激对淀粉样蛋白-β 肽诱导的大鼠海马切片中 Na,K-ATP 酶活性降低的影响
淀粉样蛋白-β 肽 (Aβ) 已被证明会导致突触功能障碍，并使神经元易受兴奋性毒性和氧化应激的影响。Na,K-ATPase 在维持细胞离子平衡中起重要作用，它可以通过 N-甲基-d-天冬氨酸 (NMDA)-一氧化氮 (NO)-环状 GMP 途径进行调节。NO 合酶 (NOS) 活性和活性氧 (ROS) 产生的破坏可能导致 Na,K-ATPase 异构体的活性发生变化，这可能对细胞有害。我们的目的是评估与 NMDA-NOS-环状 GMP 相关的 Aβ 信号通路与大鼠海马切片中α 1 -/α 2,3 -Na,K-ATP 酶活性的氧化应激。Aβ 1–40诱导大鼠海马切片中 NOS 活性的浓度依赖性增加和环磷酸鸟苷 (cGMP)、TBARS (硫代巴比妥酸反应物质) 和 3-硝基酪氨酸 (3-NT) 修饰的蛋白质水平增加。MK-801（NMDA 受体抑制剂）和 L-NAME（NOS 抑制剂）预处理完全阻断Aβ 1-40诱导的 NOS 活性和循环 GMP 水平的增加，但 TBARS 水平的变化仅被部分阻断两种化合物。Aβ 处理还降低了 Na,K-ATP 酶活性，该活性被 N-硝基-L-精氨酸甲酯盐酸盐 (L-NAME) 恢复，但不被 MK-801 预处理恢复。Aβ 诱导的酶活性降低是同种型特异性的，因为只有 α 1-Na,K-ATPase 受到影响。这些发现表明，与 α 2,3 -Na,K-ATPase 活性相关的 NMDA-NOS 信号级联的激活可能介导大鼠海马中对 Aβ 的适应性神经保护反应。
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