Rat brain N-methyl-D-aspartate receptors require multiple molecules of agonist for activation.

N-Methyl-D-aspartate (NMDA) receptors mediate important physiological and pathological processes, including long term potentiation and neuronal excitotoxicity. Elucidation of mechanisms underlying NMDA receptor functioning will promote understanding of the molecular bases of NMDA receptor-mediated processes. The localization of the phencyclidine (PCP) receptor within the ionophore of the NMDA receptor-gated ion channel permits the binding of PCP receptor ligands to serve as a functional marker of channel activation. We have previously demonstrated that the highly selective PCP receptor ligand [3H]MK-801 displays multiexponential kinetics of association, indicating that the NMDA receptor functions according to a multistate model. Using the fast component of [3H]MK-801 binding to PCP receptors as a marker for activated NMDA channels, we demonstrate here a Hill coefficient of 2 for activation of NMDA channels by L-glutamate. A multistate model of NMDA receptor functioning analogous to the model known to account for the functioning of nicotinic cholinergic and gamma-aminobutyric acidA receptors fits well to our experimental data, supporting the concept that the NMDA receptor is properly classified in the Class 1 superfamily of ligand-gated channels.