Loss of glutathione homeostasis associated with neuronal senescence facilitates TRPM2 channel activation in cultured hippocampal pyramidal neurons.
Loss of glutathione homeostasis associated with neuronal senescence facilitates TRPM2 channel activation in cultured hippocampal pyramidal neurons.
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DOI：
10.1186/1756-6606-5-11
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发表时间：
2012-04-09
期刊：
影响因子：
3.6
通讯作者：
Jackson MF
中科院分区：
文献类型：
--
作者：
Belrose JC;Xie YF;Gierszewski LJ;MacDonald JF;Jackson MF
谷胱甘肽(GSH)在神经元氧化防御中起着重要作用。在神经退行性疾病中观察到细胞GSH的耗竭，从而导致相关的氧化应激和钙离子调节失调。与神经元衰老相关的细胞GSH耗竭是否直接影响钙离子渗透途径尚不清楚。瞬时受体电位Melastatin 2(TRPM2)是一种钙离子通透性非选择性阳离子通道，表达于多种细胞类型，包括海马锥体神经元。此外，氧化应激期间TRPM2的激活与细胞死亡有关。重要的是，GSH被报道抑制TRPM2通道，这表明它们可能直接导致与神经元衰老相关的钙调节失调。在此，我们探讨了海马神经元长期培养中细胞GSH与TRPM2通道活性的关系。在全细胞电压钳记录中，我们观察到在体外培养的锥体神经元中，TRPM2电流密度随着时间的推移而增加。观察到的电流密度的增加被NAC处理，NAC是GSH合成的前体。相反，用L-BSO处理体外培养2周的细胞，通过抑制GSH的合成来耗尽GSH，增加TRPM2电流。此外，我们证明GSH通过硫醇非依赖的机制抑制TRPM2电流，并使TRPM2的细胞内激动剂ADPR产生的剂量-反应曲线移动3.5倍。这些结果表明，GSH在调节海马锥体神经元TRPM2电流中起着生理上的作用。这种相互作用可能在衰老和与GSH耗竭相关的神经系统疾病中发挥重要作用。
Glutathione (GSH) plays an important role in neuronal oxidant defence. Depletion of cellular GSH is observed in neurodegenerative diseases and thereby contributes to the associated oxidative stress and Ca2+ dysregulation. Whether depletion of cellular GSH, associated with neuronal senescence, directly influences Ca2+ permeation pathways is not known. Transient receptor potential melastatin type 2 (TRPM2) is a Ca2+ permeable non-selective cation channel expressed in several cell types including hippocampal pyramidal neurons. Moreover, activation of TRPM2 during oxidative stress has been linked to cell death. Importantly, GSH has been reported to inhibit TRPM2 channels, suggesting they may directly contribute to Ca2+ dysregulation associated with neuronal senescence. Herein, we explore the relation between cellular GSH and TRPM2 channel activity in long-term cultures of hippocampal neurons. In whole-cell voltage-clamp recordings, we observe that TRPM2 current density increases in cultured pyramidal neurons over time in vitro. The observed increase in current density was prevented by treatment with NAC, a precursor to GSH synthesis. Conversely, treatment of cultures maintained for 2 weeks in vitro with L-BSO, which depletes GSH by inhibiting its synthesis, augments TRPM2 currents. Additionally, we demonstrate that GSH inhibits TRPM2 currents through a thiol-independent mechanism, and produces a 3.5-fold shift in the dose-response curve generated by ADPR, the intracellular agonist for TRPM2. These results indicate that GSH plays a physiologically relevant role in the regulation of TRPM2 currents in hippocampal pyramidal neurons. This interaction may play an important role in aging and neurological diseases associated with depletion of GSH.
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影响因子：
3.7
作者：
Clark J;Clore EL;Zheng K;Adame A;Masliah E;Simon DK
通讯作者：
Simon DK
DOI：
10.1038/jcbfm.2010.9
发表时间：
2010-04
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
--
影响因子：
16.2
作者：
KOHR, G;ECKARDT, S;SEEBURG, PH
通讯作者：
SEEBURG, PH
影响因子：
7.4
作者：
ARUOMA, OI;HALLIWELL, B;BUTLER, J
通讯作者：
BUTLER, J
影响因子：
4.2
作者：
Aksenova, MV;Aksenov, MY;Butterfield, DA
通讯作者：
Butterfield, DA