Glycine-independent and subunit-specific potentiation of NMDA responses by extracellular Mg2+

Extracellular Mg2+, which blocks NMDA channels in a voltage-dependent manner and increases the receptor's affinity for glycine, is shown here to potentiate NMDA responses at saturating glycine concentrations. This potentiation, induced by millimolar concentrations of Mg2+, is not mimicked by Ca2+ and Ba2+ and is voltage independent. The potentiation is variable in native receptors of cultured mouse central neurons; in recombinant receptors, it is "permitted" by the NR2B subunit and prevented by the NR1 splice variant containing an N-terminal insert. Mg2+ also induces a shift of the pH sensitivity of NMDA receptors. The similarity and nonadditivity of the effects of Mg2+ and spermine suggest that Mg2+ may be the physiological agonist acting at the subunit-specific spermine site.