IDENTIFICATION BY MUTAGENESIS OF A MG2+-BLOCK SITE OF THE NMDA RECEPTOR CHANNEL

THE N-methyl-D-aspartate (NMDA) receptor channel is highly permeable to Ca2+ but is blocked by Mg2+ in a voltage-dependent manner1-4. These characteristics are essential for the NMDA receptor channel to mediate the induction of long-term potentiation of synaptic efficacy, a form of activity-dependent synaptic plasticity thought to underlie memory, learning and development5-8. Recent studies have revealed the molecular and functional diversity of the NMDA receptor channel subunits, which are classified into the epsilon and zeta families according to the amino-acid sequence homology9-12. Here we report that replacement by glutamine of asparagine 598 in putative transmembrane segment M2 of the zeta-1 subunit, strongly reduces the sensitivity of the heteromeric epsilon-2/zeta-1 NMDA receptor channel to Mg2+ block. The corresponding mutation of the epsilon-2 subunit has a similar effect. Furthermore, the heteromeric epsilon-2/zeta-1 NMDA receptor channel with the mutation on both subunits shows greatly reduced sensitivity to MK-801, a channel blocker of the NMDA receptor channel13,14, but is still susceptible to inhibition by Zn2+ 15,16. These findings suggest that the conserved asparagine residue in segment M2 constitutes a Mg2+-block site of the NMDA receptor channel, and that the MK-801 site overlaps the Mg2+ site.