Changes in NMDA Receptor Function in Rapid Ischemic Tolerance: A Potential Role for Tri-Heteromeric NMDA Receptors.
Changes in NMDA Receptor Function in Rapid Ischemic Tolerance: A Potential Role for Tri-Heteromeric NMDA Receptors.
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DOI：
10.3390/biom12091214
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发表时间：
2022-09-01
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
--
作者：
在这项研究中，我们描述了NMDA受体功能在短暂的非损伤性缺血应激（缺血预处理）下的生物物理变化。电生理研究表明，预处理后大鼠皮层神经元的NMDA受体功能降低。这种功能变化不是由于受体逆转电位的变化，而是脱敏性的增加。我们对NMDA诱发电流进行了浓度-反应分析，结果表明，预处理神经元显示出NMDA诱发电流的效力降低，Mg2+敏感性增加，但甘氨酸敏感性没有变化。拮抗剂研究表明，GluN2B拮抗剂具有变变作用模式（ifenprodil和R-25-6981），但GluR2A和2B受体的竞争性拮抗剂（NVP-AMM077和conantoin - g）似乎具有类似的阻断电流的效力。生化研究表明，膜表面GluN2B亚基减少，GluN2A与GluN2B亚基的共免疫沉淀增加，提示三异聚体受体的形成。最后，我们发现用茉莉烯内酯阻断肌动蛋白重塑是一种快速缺血耐受的机制，可以阻止NMDA受体功能的改变和GluN2A和2B亚基的共免疫沉淀。总之，本研究表明，预处理缺血后NMDA受体功能的改变与快速缺血耐受中的神经保护有关。
In this study, we characterize biophysical changes in NMDA receptor function in response to brief non-injurious ischemic stress (ischemic preconditioning). Electrophysiological studies show NMDA receptor function is reduced following preconditioning in cultured rat cortical neurons. This functional change is not due to changes in the reversal potential of the receptor, but an increase in desensitization. We performed concentration–response analysis of NMDA-evoked currents, and demonstrate that preconditioned neurons show a reduced potency of NMDA to evoke currents, an increase in Mg2+ sensitivity, but no change in glycine sensitivity. Antagonists studies show a reduced inhibition of GluN2B antagonists that have an allosteric mode of action (ifenprodil and R-25-6981), but competitive antagonists at the GluR2A and 2B receptor (NVP-AMM077 and conantokin-G) appear to have similar potency to block currents. Biochemical studies show a reduction in membrane surface GluN2B subunits, and an increased co-immunoprecipitation of GluN2A with GluN2B subunits, suggestive of tri-heteromeric receptor formation. Finally, we show that blocking actin remodeling with jasplakinolide, a mechanism of rapid ischemic tolerance, prevents NMDA receptor functional changes and co-immunoprecipitation of GluN2A and 2B subunits. Together, this study shows that alterations in NMDA receptor function following preconditioning ischemia are associated with neuroprotection in rapid ischemic tolerance.
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DOI：
10.1056/nejmcibr0902052
发表时间：
2009-07-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Li F;Tsien JZ
通讯作者：
Tsien JZ
影响因子：
16.2
作者：
Hansen KB;Ogden KK;Yuan H;Traynelis SF
通讯作者：
Traynelis SF
影响因子：
25
作者：
Hardingham, GE;Fukunaga, Y;Bading, H
通讯作者：
Bading, H
影响因子：
64.8
作者：
Chatterton, JE;Awobuluyi, M;Zhang, DX
通讯作者：
Zhang, DX
影响因子：
5
作者：
Boireau, A;Malgouris, C;Doble, A
通讯作者：
Doble, A