Department of Neuroscience and Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA.
Department of Neuroscience and Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Neuropharmacology. 2018 Jul 15;137:344-358. doi: 10.1016/j.neuropharm.2018.05.017. Epub 2018 May 12.
Memantine and ketamine are NMDA receptor (NMDAR) open channel blockers that are thought to act via similar mechanisms at NMDARs, but exhibit divergent clinical effects. Both drugs act by entering open NMDARs and binding at a site deep within the ion channel (the deep site) at which the endogenous NMDAR channel blocker Mg also binds. Under physiological conditions, Mg increases the ICs of memantine and ketamine through competition for binding at the deep site. Memantine also can inhibit NMDARs after associating with a second site accessible in the absence of agonist, a process termed second site inhibition (SSI) that is not observed with ketamine. Here we investigated the effects of 1 mM Mg on recovery from inhibition by memantine and ketamine, and on memantine SSI, of the four main diheteromeric NMDAR subtypes. We found that: recovery from memantine inhibition depended strongly on the concentration of memantine used to inhibit the NMDAR response; Mg accelerated recovery from memantine and ketamine inhibition through distinct mechanisms and in an NMDAR subtype-dependent manner; and Mg occupation of the deep site disrupted memantine SSI in a subtype-dependent manner. Our results support the hypothesis that memantine associates with, but does not inhibit at the second site. After associating with the second site, memantine can either slowly dissociate directly to the extracellular solution, or transit to the deep site, resulting in typical channel block. Memantine's relatively slow dissociation from the second site underlies the dependence of NMDAR recovery from inhibition on both memantine concentration and on Mg.
美金刚和氯胺酮是 NMDA 受体 (NMDAR) 开放通道阻滞剂，它们被认为通过 NMDAR 相似的机制发挥作用，但表现出不同的临床效果。这两种药物的作用机制都是通过进入开放的 NMDAR 并与离子通道内的一个深部位点（深部位点）结合，内源性 NMDAR 通道阻滞剂 Mg 也结合在该部位点。在生理条件下，Mg 通过与深部位点竞争结合，增加了美金刚和氯胺酮的 IC50。美金刚还可以在没有激动剂的情况下与第二个可及位点结合后抑制 NMDAR，这个过程被称为第二结合位点抑制（SSI），而氯胺酮则没有观察到这种作用。在这里，我们研究了 1 mM Mg 对美金刚和氯胺酮抑制的恢复作用，以及对四种主要的异二聚体 NMDAR 亚型的美金刚 SSI 的影响。我们发现：美金刚抑制的恢复强烈依赖于用于抑制 NMDAR 反应的美金刚浓度；Mg 通过不同的机制和 NMDAR 亚型依赖性加速了美金刚和氯胺酮抑制的恢复；Mg 占据深部位点以 NMDAR 亚型依赖性的方式破坏了美金刚 SSI。我们的结果支持了这样的假设，即美金刚与第二个结合位点结合，但不在该位点抑制。与第二个结合位点结合后，美金刚可以直接缓慢地从细胞外溶液中解离，或者转位到深部位点，从而导致典型的通道阻断。美金刚从第二个结合位点的相对缓慢解离是 NMDAR 从抑制中恢复的依赖性的基础，这种依赖性既依赖于美金刚的浓度，也依赖于 Mg。
