Recovery of NMDA receptor currents from MK-801 blockade is accelerated by Mg²⁺ and memantine under conditions of agonist exposure

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• 作者：Sean McKay ; C. Peter Bengtson ; Hilmar Bading ; David J.A. Wyllie ; Giles E. Hardingham
• 关键词：Glutamate receptor ; NMDA receptor ; Pharmacology ; Synapse ; Extrasynaptic ; Excitotoxicity ; MK-801 ; Magnesium
• 刊名：Neuropharmacology
• 出版年：2013
• 出版时间：November, 2013
• 年：2013
• 卷：74
• 期：Complete
• 页码：119-125
• 全文大小：876 K

文摘

MK-801 is a use-dependent NMDA receptor open channel blocker with a very slow off-rate. These properties can be exploited to ¡®pre-block¡¯ a population of NMDARs, such as synaptic ones, enabling the selective activation of a different population, such as extrasynaptic NMDARs. However, the usefulness of this approach is dependent on the stability of MK-801 blockade after washout. We have revisited this issue, and confirm that recovery of NMDAR currents from MK-801 blockade is enhanced by channel opening by NMDA, and find that it is further increased when Mg²⁺ is also present. In the presence of Mg²⁺, 50 % recovery from MK-801 blockade is achieved after 10¡ä of 100?¦ÌM NMDA, or 30¡ä of 15?¦ÌM NMDA exposure. In Mg²⁺-free medium, NMDA-induced MK-801 dissociation was found to be much slower. Memantine, another PCP-site antagonist, could substitute for Mg²⁺ in accelerating the unblock of MK-801 in the presence of NMDA. This suggests a model whereby, upon dissociation from its binding site in the pore, MK-801 is able to re-bind in a process antagonized by Mg²⁺ or another PCP-site antagonist. Finally we show that even when all NMDARs are pre-blocked by MK-801, incubation of neurons with 100?¦ÌM NMDA in the presence of Mg²⁺ for 2.5?h triggers sufficient unblocking to kill >80 % of neurons. We conclude that while synaptic MK-801 ¡®pre-block¡¯ protocols are useful for pharmacologically assessing synaptic vs. extrasynaptic contributions to NMDAR currents, or studying short-term effects, it is problematic to use this technique to attempt to study the effects of long-term selective extrasynaptic NMDAR activation.

This article is part of the Special Issue entitled ¡®Glutamate Receptor-Dependent Synaptic Plasticity¡¯.