D. C. Wrighton and E. J. Baker contributed equally to this work. This paper has online supplemental material.
Mg2+ and memantine block of rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes
Article first published online: 2 JAN 2008
The Journal of Physiology
Volume 586, Issue 1, pages 211–225, January 2008
How to Cite
Wrighton, D. C., Baker, E. J., Chen, P. E. and Wyllie, D. J. A. (2008), Mg2+ and memantine block of rat recombinant NMDA receptors containing chimeric NR2A/2D subunits expressed in Xenopus laevis oocytes. The Journal of Physiology, 586: 211–225. doi: 10.1113/jphysiol.2007.143164
- Issue published online: 2 JAN 2008
- Article first published online: 2 JAN 2008
- (Received 20 August 2007; accepted after revision 23 October 2007; first published online 25 October 2007)
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.