Delayed calcium dysregulation in neurons requires both the NMDA receptor and the reverse Na+/Ca2+ exchanger.
Delayed calcium dysregulation in neurons requires both the NMDA receptor and the reverse Na+/Ca2+ exchanger.
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DOI：
10.1016/j.nbd.2011.12.051
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发表时间：
2012-04
影响因子：
6.1
通讯作者：
Brustovetsky, Nickolay
中科院分区：
文献类型：
--
作者：
Brittain, Matthew K.;Brustovetsky, Tatiana;Sheets, Patrick L.;Brittain, Joel M.;Khanna, Rajesh;Cummins, Theodore R.;Brustovetsky, Nickolay
谷氨酸诱导的迟发性钙调节障碍(DCD)是导致神经元死亡的原因之一。DCD的发病机制尚不清楚，但可能通过N-甲基-D-天冬氨酸受体(NMDAR)和/或反向质膜Na~+/Ca~(2+)交换器(NCXrev)参与钙离子内流。然而，NMDAR和NCXrev在谷氨酸诱导的DCD中的作用程度尚不确定。在这里，我们表明NMDAR和NCXrev对于暴露于兴奋性毒性谷氨酸的神经元中的DCD都是关键的。在培养的大鼠海马神经细胞上，25μ-M谷氨酸可产生双氰胺，并伴有胞浆Na+([Na+]c)和质膜去极化的持续增加。非竞争性NMDAR抑制剂MK801和美金刚在谷氨酸后不久加入，可完全阻止DCD，而竞争性NMDAR抑制剂AP-5则不能预防DCD。所有受试的抑制剂均未降低升高的[Na+]c或恢复质膜电位。在革兰西丁逆转NCX的实验中，MK801和美金刚对NCXrev有较强的抑制作用，而AP-5的抑制作用较弱。在电生理膜片钳实验中，MK801和美金刚可抑制NCXrev介导的离子电流，而AP-5则不能。因此，除NMDAR外，MK801和美金刚还抑制NCXrev。用KB-R7943抑制NCXrev，或通过破坏质膜上的Na+梯度，或用5-(N-乙基-N-异丙基)阿米洛利(EIPA)抑制Na+/H+交换，从而阻止[Na+]c的增加，都不能阻止DCD。但联合应用AP-5抑制NCXrev和阻断NMDAR可完全阻止DCD的发生。总体而言，我们的数据表明，NMDAR和NCXrev对谷氨酸暴露的神经元中的DCD都是必不可少的，抑制单独的机制不足以防止钙调节失调。
Glutamate-induced delayed calcium dysregulation (DCD) is a causal factor leading to neuronal death. The mechanism of DCD is not clear but Ca2+ influx via N-methyl-D-aspartate receptors (NMDAR) and/or the reverse plasmalemmal Na+/Ca2+ exchanger (NCXrev) could be involved in DCD. However, the extent to which NMDAR and NCXrev contribute to glutamate-induced DCD is uncertain. Here, we show that both NMDAR and NCXrev are critical for DCD in neurons exposed to excitotoxic glutamate. In rat cultured hippocampal neurons, 25μM glutamate produced DCD accompanied by sustained increase in cytosolic Na+ ([Na+]c) and plasma membrane depolarization. MK801 and memantine, noncompetitive NMDAR inhibitors, added shortly after glutamate, completely prevented DCD whereas AP-5, a competitive NMDAR inhibitor, failed to protect against DCD. None of the tested inhibitors lowered elevated [Na+]c or restored plasma membrane potential. In the experiments with NCX reversal by gramicidin, MK801 and memantine robustly inhibited NCXrev while AP-5 was much less efficacious. In electrophysiological patch-clamp experiments MK801 and memantine inhibited NCXrev-mediated ion currents whereas AP-5 failed. Thus, MK801 and memantine, in addition to NMDAR, inhibited NCXrev. Inhibition of NCXrev either with KB-R7943, or by collapsing Na+ gradient across the plasma membrane, or by inhibiting Na+/H+ exchanger with 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and thus preventing the increase in [Na+]c failed to preclude DCD. However, NCXrev inhibition combined with NMDAR blockade by AP-5 completely prevented DCD. Overall, our data suggest that both NMDAR and NCXrev are essential for DCD in glutamate-exposed neurons and inhibition of individual mechanism is not sufficient to prevent calcium dysregulation.
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影响因子：
4.7
作者：
Czyz, A;Baranauskas, G;Kiedrowski, L
通讯作者：
Kiedrowski, L
影响因子：
7.3
作者：
Brustovetsky, Tatiana;Brittain, Matthew K.;Brustovetsky, Nickolay
通讯作者：
Brustovetsky, Nickolay
DOI：
10.1042/bss0660085
发表时间：
1999-01-01
期刊：
MITOCHONDRIA AND CELL DEATH
影响因子：
--
作者：
Greenamyre, JT;MacKenzie, G;Stephans, SE
通讯作者：
Stephans, SE
DOI：
10.1002/neu.480230915
发表时间：
1992-11-01
期刊：
JOURNAL OF NEUROBIOLOGY
影响因子：
--
作者：
CHOI, DW
通讯作者：
CHOI, DW
影响因子：
4.8
作者：
Chalmers, S;Nicholls, DG
通讯作者：
Nicholls, DG