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The Journal of Neuroscience, March 4, 2009, 29(9):2774-2779; doi:10.1523/JNEUROSCI.3703-08.2009

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Brief Communications
Mg²⁺ Imparts NMDA Receptor Subtype Selectivity to the Alzheimer's Drug Memantine

Shawn E. Kotermanski and Jon W. Johnson

Department of Neuroscience and Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260

Correspondence should be addressed to Jon W. Johnson, Department of Neuroscience, A210 Langley Hall, University of Pittsburgh, Pittsburgh, PA 15260. Email: jjohnson{at}pitt.edu

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 Mg²⁺ (Mg). Mg 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 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 Mg. 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.

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Received Aug. 5, 2008; revised Jan. 31, 2009; accepted Feb. 2, 2009.

Correspondence should be addressed to Jon W. Johnson, Department of Neuroscience, A210 Langley Hall, University of Pittsburgh, Pittsburgh, PA 15260. Email: jjohnson{at}pitt.edu

This article has been cited by other articles:

				S. E. Kotermanski, J. T. Wood, and J. W. Johnson Memantine binding to a superficial site on NMDA receptors contributes to partial trapping J. Physiol., October 1, 2009; 587(19): 4589 - 4604. [Abstract] [Full Text] [PDF]

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