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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 586/1/211    most recent jphysiol.2007.143164v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wrighton, D. C. Articles by Wyllie, D. J. A. Search for Related Content PubMed PubMed Citation Articles by Wrighton, D. C. Articles by Wyllie, D. J. A. Related Collections Neuroscience

¹ Centre for Neuroscience Research, Hugh Robson Building, University of Edinburgh, George Square, Edinburgh EH8 9XD, UK

N-methyl-D-aspartate receptors (NMDARs) display differences in their sensitivity to the channel blockers Mg²⁺ and memantine that are dependent on the identity of the NR2 subunit present in the receptor–channel complex. This study used two-electrode voltage-clamp recordings from Xenopus laevis oocytes expressing recombinant NMDARs to investigate the actions of Mg²⁺ and memantine at the two NMDARs displaying the largest differences in sensitivity to these blockers, namely NR1/NR2A and NR1/NR2D NMDARs. In addition, NR2A/2D chimeric subunits have been employed to examine the effects of pore-forming elements and ligand-binding domains (LBD) on the potency of the block produced by each of these inhibitors. Our results show that, as previously documented, NR2D-containing NMDARs are less sensitive to voltage-dependent Mg²⁺ block than their NR2A-containing counterparts. The reduced sensitivity is determined by the M1M2M3 membrane-associated regions, as replacing these regions in NR2A subunits with those found in NR2D subunits results in a 10-fold reduction in Mg²⁺ potency. Intriguingly, replacing the NR2A LBD with that from NR2D subunits results in a 2-fold increase in Mg²⁺ potency. Moreover, when responses mediated by NR1/NR2A NMDARs are evoked by the partial agonist homoquinolinate, rather than glutamate, Mg²⁺ also displays an increased potency. Memantine block of glutamate-evoked currents is most potent at NR1/NR2D NMDARs, but no differences are observed in its ability to inhibit NR2A-containing or NR2A/2D chimeric NMDARs. We suggest that the potency of block of NMDARs by Mg²⁺ is influenced not only by pore-forming regions but also the LBD and the resulting conformational changes that occur following agonist binding.

(Received 20 August 2007; accepted after revision 23 October 2007; first published online 25 October 2007)
Corresponding author D. J. A. Wyllie: Centre for Neuroscience Research, Hugh Robson Building, University of Edinburgh, George Square, Edinburgh EH8 9XD, UK. Email: dwyllie1{at}staffmail.ed.ac.uk

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