Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine.
Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine.
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DOI：
10.1523/jneurosci.3703-08.2009
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发表时间：
2009-03-04
期刊：
影响因子：
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通讯作者：
Johnson JW
中科院分区：
文献类型：
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作者：
Kotermanski SE;Johnson JW
N-甲基-d-天冬氨酸受体（NMDAR）介导神经元间通讯，广泛参与神经系统生理学和病理学。美金刚是一种阻断 NMDAR 形成的离子通道的药物，是一种广泛用于治疗阿尔茨海默病的药物。美金刚作用机制的研究主要集中在成人大脑皮层中表达最高的 NMDAR 亚型、NR1/2A 和 NR1/2B 受体，而很大程度上忽略了与细胞外 Mg2+ (Mg2+o) 的相互作用。 Mg2+o 是一种内源性 NMDAR 通道阻断剂，结合在美金刚的结合位点附近。我们报道，在接近静止的膜电压下，生理浓度（1 mM）的 Mg2+o 可将美金刚对 NR1/2A 和 NR1/2B 受体的抑制作用降低近 20 倍。相比之下，美金刚对其他主要 NMDAR 亚型 NR1/2C 和 NR1/2D 受体的抑制仅降低约 3 倍。因此，治疗美金刚浓度对 NR1/2A 或 NR1/2B 受体活性的影响可以忽略不计，但对 NR1/2C 和 NR1/2D 受体的影响显着。定量模型表明，1 mM Mg2+o 也会改变美金刚抑制的电压依赖性。我们报告了 NMDAR 通道阻滞剂氯胺酮（一种用于模拟精神分裂症的药物）的类似结果。这些结果表明，目前假设的美金刚和氯胺酮作用机制应该重新考虑，并且 NR1/2C 和/或 NR1/2D 受体在皮质生理学和病理学中发挥比以前认识到的更重要的作用。
N-methyl-d-aspartate receptors (NMDARs) mediate interneuronal communication and are broadly involved in nervous system physiology and pathology. Memantine, a drug that blocks the ion channel formed by NMDARs, is a widely-prescribed treatment of Alzheimers's disease. Research on memantine's mechanism of action has focused on the NMDAR subtypes most highly expressed in adult cerebral cortex, NR1/2A and NR1/2B receptors, and has largely ignored interactions with extracellular Mg2+ (Mg2+o). Mg2+o is an endogenous NMDAR channel blocker that binds near memantine's binding site. We report that a physiological concentration (1 mM) of Mg2+o decreased memantine inhibition of NR1/2A and NR1/2B receptors nearly 20-fold at a membrane voltage near rest. In contrast, memantine inhibition of the other principal NMDAR subtypes, NR1/2C and NR1/2D receptors, was decreased only ∼3-fold. As a result, therapeutic memantine concentrations should have negligible effects on NR1/2A or NR1/2B receptor activity but pronounced effects on NR1/2C and NR1/2D receptors. Quantitative modeling showed that the voltage dependence of memantine inhibition also is altered by 1 mM Mg2+o. We report similar results with the NMDAR channel blocker ketamine, a drug used to model schizophrenia. These results suggest that currently hypothesized mechanisms of memantine and ketamine action should be reconsidered, and that NR1/2C and/or NR1/2D receptors play a more important role in cortical physiology and pathology than previously appreciated.