Mg2+ imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine.
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.
Kotermanski
Shawn E
SE
Department of Neuroscience and Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA.
Johnson
Jon W
JW
D000544:Alzheimer Disease / Q000188:drug therapy*; D002478:Cells, Cultured; D003627:Data Interpretation, Statistical; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007649:Ketamine / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology*; D008559:Memantine / Q000494:pharmacology* / Q000627:therapeutic use*; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D014162:Transfection
D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D007649:Ketamine; D008274:Magnesium; D008559:Memantine