A mutation that alters magnesium block of N-methyl-D-aspartate receptor channels

N-Methyl-D-aspartate (NMDA) receptors are blocked at hyperpolarizing potentials by extracellular Mg ions. Here we present a detailed kinetic analysis of the Mg block in recombinant wild-type and mutant NMDA receptors. We find that the Mg binding site is the same in the wild-type and native hippocampal NMDA receptor channels. In the mutant channels, however, Mg ions bind with a 10-fold lower affinity. On the basis of these results, we propose that the energy well at the Mg binding site in the mutants is shallow and the binding is unstable because of an increase in the rate of dissociation. We postulate that the dipole formed by the amide group of asparagine 614 of the epsilon 1 subunit contributes to the structure of the binding site but predict that additional ligands will be involved in coordinating Mg ions.