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Mg 2+ and memantine block of rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes
Author(s) -
Wrighton David C.,
Baker Edward J.,
Chen Philip E.,
Wyllie David J. A.
Publication year - 2008
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2007.143164
Subject(s) - xenopus , memantine , nmda receptor , recombinant dna , receptor , chemistry , protein subunit , microbiology and biotechnology , neuroscience , biology , biophysics , biochemistry , gene
N ‐methyl‐ d ‐aspartate receptors (NMDARs) display differences in their sensitivity to the channel blockers Mg 2+ 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 Mg 2+ 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 Mg 2+ 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 Mg 2+ potency. Intriguingly, replacing the NR2A LBD with that from NR2D subunits results in a ∼2‐fold increase in Mg 2+ potency. Moreover, when responses mediated by NR1/NR2A NMDARs are evoked by the partial agonist homoquinolinate, rather than glutamate, Mg 2+ 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 Mg 2+ is influenced not only by pore‐forming regions but also the LBD and the resulting conformational changes that occur following agonist binding.