Ifenprodil, a NR2B-selective antagonist of NMDA receptor, inhibits reverse Na+/Ca2+ exchanger in neurons.
Ifenprodil, a NR2B-selective antagonist of NMDA receptor, inhibits reverse Na+/Ca2+ exchanger in neurons.
复制标题
DOI：
10.1016/j.neuropharm.2012.07.012
复制
发表时间：
2012-11
影响因子：
4.7
通讯作者：
Brustovetsky N
中科院分区：
文献类型：
--
作者：
Brittain MK;Brustovetsky T;Brittain JM;Khanna R;Cummins TR;Brustovetsky N
谷氨酸诱导的迟发性钙调节障碍(DCD)与兴奋性毒性神经元死亡有关。DCD的发病机制尚不完全清楚，但已有研究提出，外源性钙离子的过度内流是DCD的重要因素。谷氨酸受体NMDA亚型(NMDAR)和质膜Na+/Ca~(2+)交换器(NCXrev)在DCD中起重要作用。在“年轻”神经元体外培养6-8天(6-8天)的实验中，含NR2A的NMDAR低表达，含NR2B的NMDAR的抑制剂异丙苯地尔可完全阻止DCD，而另一种优先与NR2A-NMDAR相互作用的NMDAR拮抗剂PEAQX则无作用。对于较老的神经元(13-16个DIV)，其中NR2A-和NR2B-NMDAR在更大程度上表达，单独应用异丙苯地尔和PEAQX都不能预防DCD。然而，联合应用依芬地尔和PEAQX可完全避免DCD。依芬地尔和依芬普地尔样的NR2B-NMDAR拮抗剂Ro 25-6981和Co 101244，而不是PEAQX或AP-5，可抑制主要由NCXrev介导的革兰尼丁和Na+/NMDG替代诱导的细胞内钙离子的增加。提示依芬地尔、Ro25-6981和Co 101244对NCXrev有抑制作用。依芬地尔抑制NCXrev的能力与其预防DCD的疗效相关，强调了NCXrev在DCD中的重要作用。总体而言，我们的数据表明，NR2A-和NR2B-NMDARs都参与了“老年”神经元的DCD，有必要同时抑制NMDARs和NCXrev，以防止谷氨酸诱导的DCD。
Glutamate-induced delayed calcium dysregulation (DCD) is causally linked to excitotoxic neuronal death. The mechanisms of DCD are not completely understood, but it has been proposed that the excessive influx of external Ca2+ is essential for DCD. The NMDA-subtype of glutamate receptor (NMDAR) and the plasmalemmal Na+/Ca2+ exchanger operating in the reverse mode (NCXrev) have been implicated in DCD. In experiments with “younger” neurons, 6-8 days in vitro (6-8 DIV), in which the NR2A-containing NMDAR expression is low, ifenprodil, an inhibitor of NR2B-containing NMDAR, completely prevented DCD whereas PEAQX, another NMDAR antagonist that preferentially interacts with NR2A-NMDAR, was without effect. With “older” neurons (13-16 DIV), in which NR2A- and NR2B-NMDARs are expressed to a greater extent, both ifenprodil and PEAQX applied separately failed to prevent DCD. However, combined application of ifenprodil and PEAQX completely averted DCD. Ifenprodil and ifenprodil-like NR2B-NMDAR antagonists Ro 25-6981 and Co 101244 but not PEAQX or AP-5 inhibited gramicidin- and Na+/NMDG-replacement-induced increases in cytosolic Ca2+ mediated predominantly by NCXrev. This suggests that ifenprodil, Ro 25-6981, and Co 101244 inhibit NCXrev. The ability of ifenprodil to inhibit NCXrev correlates with its efficacy in preventing DCD and emphasizes an important role of NCXrev in DCD. Overall our data suggest that both NR2A- and NR2B-NMDARs are involved in DCD in “older” neurons, and it is necessary to inhibit both NMDARs and NCXrev to prevent glutamate-induced DCD.
登录
查看更多内容
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
影响因子：
3.6
作者：
Hoyt, KR;Arden, SR;Reynolds, IJ
通讯作者：
Reynolds, IJ
影响因子：
4.8
作者：
Iwamoto, T;Watano, T;Shigekawa, M
通讯作者：
Shigekawa, M
影响因子：
7.3
作者：
Feng, BH;Tse, HW;Monaghan, DT
通讯作者：
Monaghan, DT