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Internal Mg²⁺ block of recombinant NMDA channels mutated within the selectivity filter and expressed in Xenopus oocytes

Jürgen Kupper, Philippe Ascher and Jacques Neyton

1. The NMDA receptor channel is blocked by both external and internal Mg²⁺ ions, which are assumed to bind inside the channel on each side of a central barrier. We have analysed the internal Mg²⁺ block in recombinant NR1-NR2A NMDA receptors expressed in Xenopus oocytes. We have determined the effects of mutations of two asparagines that line the selectivity filter of the channel, one located within the NR1 subunit (N598) and the other within the NR2A subunit (N596).

2. The whole-cell current-voltage relation of wild-type NMDA channels shows inward rectification that reflects the voltage-dependent block produced by the internal Mg²⁺ of the oocyte. This inward rectification is slightly reduced in the NR2 mutant (N596S) but is abolished in the NR1 mutants (N598Q and N598S). This suggests that the NR1 asparagine plays a larger role than the NR2 asparagine in controlling the internal Mg²⁺ block.

3. Single-channel current-voltage relations confirm that the internal Mg²⁺ block is reduced in both the NR1 and NR2 mutants. However, the reduction is small and is similar for the two families of mutants.

4. The discrepancy between whole-cell and single-channel data is partly due to differential effects of internal Mg²⁺ on the open probabilities of the two conductance states present in NR1 mutant channels.

5. The results suggest that mutations of NR1 and NR2 asparagines lower the central barrier to Mg²⁺. An additional contribution of the NR2 asparagine to the external Mg²⁺ binding site (and possibly to the external barrier that controls access to this site) may account for the marked relief of external Mg²⁺ block produced by the NR2 mutation.

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