Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2009 Mar 4;29(9):2774-9.
doi: 10.1523/JNEUROSCI.3703-08.2009.

Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine

Shawn E Kotermanski  1 , Jon W Johnson
Affiliations

Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine

Shawn E Kotermanski et al. J Neurosci. .

Abstract

N-methyl-D-aspartate receptors (NMDARs) mediate interneuronal communication and are broadly involved in nervous system physiology and pathology (Dingledine et al., 1999). Memantine, a drug that blocks the ion channel formed by NMDARs, is a widely prescribed treatment of Alzheimer's disease (Schmitt, 2005; Lipton, 2006; Parsons et al., 2007). 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 (Cull-Candy and Leszkiewicz, 2004), and has largely ignored interactions with extracellular Mg(2+) (Mg(2+)(o)). Mg(2+)(o) is an endogenous NMDAR channel blocker that binds near memantine's binding site (Kashiwagi et al., 2002; Chen and Lipton, 2005). We report that a physiological concentration (1 mM) of Mg(2+)(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 approximately 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 Mg(2+)(o). We report similar results with the NMDAR channel blocker ketamine, a drug used to model schizophrenia (Krystal et al., 2003). 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.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Effects of Mg2+o and NMDAR subunit composition on memantine inhibition. A, Schematic of an NMDAR showing the four subunits of a functional receptor (left) and transmembrane structure of an NR1 and an NR2 subunit (right). The approximate channel blocking region of Mg2+o, memantine, and ketamine (filled black circle with +) is shown near the asparagines (filled red circles) involved in blocker binding. B, D, Overlay of NR1/2A (black) and NR1/2D (red) receptor current traces recorded from transfected HEK293T cells in 0 (B) and 1 mm (D) Mg2+o during application of the indicated memantine concentrations ([Mem]). Peak inward NR1/2A receptor currents here and in Figure 2 are truncated. Current noise in Figures 1 and 2 appears lower in Mg2+o because Mg2+ block shifts noise to higher (more heavily filtered) frequencies. Experiments similar to those shown in A and B were performed with NR1/2B and NR1/2C receptors (examples not shown). C, E, Memantine concentration-inhibition curves recorded in 0 (C) and 1 mm (E) Mg2+o from the indicated NMDAR subtypes. Gray shaded areas represent estimated extracellular memantine concentration range (0.5–1 μm) during therapeutic treatment (Parsons et al., 2007).
Figure 2.
Figure 2.
Effects of Mg2+o and NMDAR subunit composition on ketamine inhibition. A, C, Overlay of NR1/2A (black) and NR1/2D (red) receptor current traces recorded in 0 (A) and 1 mm (C) Mg2+o during application of the indicated concentrations of (+/−)ketamine ([Ket]). Similar experiments were performed with NR1/2B and NR1/2C receptors (examples not shown). B, D, Ketamine concentration-inhibition curves recorded in 0 (B) and 1 mm (D) Mg2+o from the indicated NMDAR subtypes.
Figure 3.
Figure 3.
Model predictions of Mg2+o and NMDAR subtype effects on voltage dependence of memantine and ketamine inhibition. A, B, Modeled voltage dependence of memantine (A) and ketamine (B) IC50s in 0 and 1 mm Mg2+o, corrected for incomplete competition between memantine or ketamine and Mg2+o (by using equivalent [Mg2+o ]s). For clarity, only plots for NR1/2A (which resemble plots for NR1/2B) and for NR1/2D (which resemble plots for NR1/2C) receptors are shown. Points at −66 and −26 mV show measured IC50 values in 0 (filled circles) and/or 1 mm (open circles) Mg2+o. The two points at −26 mV in B are nearly identical. For details of model and calculation of equivalent [Mg2+o ], see supplemental material (available at www.jneurosci.org).
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Annetta MG, Iemma D, Garisto C, Tafani C, Proietti R. Ketamine: new indications for an old drug. Curr Drug Targets. 2005;6:789–794. - PubMed
    1. Aracava Y, Pereira EF, Maelicke A, Albuquerque EX. Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than N-methyl-D-aspartate receptors in rat hippocampal neurons. J Pharmacol Exp Ther. 2005;312:1195–1205. - PubMed
    1. Bell KF, Claudio Cuello A. Altered synaptic function in Alzheimer's disease. Eur J Pharmacol. 2006;545:11–21. - PubMed
    1. Blanpied TA, Boeckman FA, Aizenman E, Johnson JW. Trapping channel block of NMDA-activated responses by amantadine and memantine. J Neurophysiol. 1997;77:309–323. - PubMed
    1. Chen HS, Lipton SA. Pharmacological implications of two distinct mechanisms of interaction of memantine with N-methyl-D-aspartate-gated channels. J Pharmacol Exp Ther. 2005;314:961–971. - PubMed

Publication types

MeSH terms