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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Modulation by magnesium of the affinity of NMDA receptors for glycine in murine hippocampal neurones.

1. The effects of the divalent cation Mg2+ on NMDA currents recorded from cultured fetal mouse and acutely isolated neonatal rat hippocampal neurones were studied using the whole-cell patch-clamp technique. 2. Current-voltage relations were measured in the presence or absence of applied Mg2+ and added glycine. NMDA-evoked currents were studied in the absence or in a low concentration (0.2 mM) of applied Ca2+ in order to minimize Ca(2+)-dependent inactivation of the responses. Mg2+ unexpectedly enhanced NMDA-activated currents at positive membrane potentials. At negative membrane potentials Mg2+ caused a previously characterized voltage-dependent block of inward NMDA-activated currents. 3. The potentiation by Mg2+ of outward currents activated by NMDA was concentration dependent (EC50, approximately 3 mM; Hill coefficient, approximately 2). Mg2+ also reduced the desensitization of the NMDA receptor. The maximal enhancement of steady-state NMDA-activated currents was 2.7-fold and at 6 mM the time constant of desensitization was doubled. 4. Comparisons of concentration-response curves for glycine and 7-chloro-kynurenic acid demonstrated that Mg2+ significantly increased the affinity of the NMDA receptor for glycine. The EC50 for glycine was 380 nM in the absence of Mg2+ and 163 nM in 3 mM Mg2+. Mg2+ had little effect on the forward rate of the glycine response but halved the off-rate (2.34 to 1.15 s-1) and thus similarly reduced the apparent dissociation constant. 5. There was a good correlation between the concentration of extracellular Ca2+ and a reduction in the time constant of the glycine-sensitive component of NMDA receptor desensitization. Ca2+ could enhance these NMDA-activated currents briefly following exposure to high concentrations of Ca2+. These results are consistent with a Ca(2+)-dependent enhancement of the affinity of the NMDA receptor for glycine. 6. Mg2+ can enhance NMDA-mediated currents and reduce desensitization of this receptor by allosterically interacting with the glycine binding site. This interaction may be a key physiological mechanism through which modulation of the NMDA receptor is achieved.[1]


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