ACTIVATION-RELATED AND ACTIVATION-INDEPENDENT EFFECTS OF POLYAMINES ON PHENCYCLIDINE RECEPTOR-BINDING WITHIN THE N-METHYL-D-ASPARTATE RECEPTOR COMPLEX

The phencyclidine (PCP) receptor is located within the N-methyl-D-aspa rtate (NMDA) receptor-gated ion channel. The functional state of the N MDA receptor complex thus influences parameters of radioligand binding to the PCP receptor, and PCP receptor ligands can serve as in vitro p robes for elucidation of NMDA receptor activation mechanisms. PCP rece ptor binding is stimulated by NMDA receptor agonists such as L-glutama te and also by distinct classes of modulatory agents such as glycine-l ike amino acids and polyamines such as spermidine (SPD). The present s tudy utilizes a kinetic approach permitting differentiation of PCP rec eptor binding within closed and activated conformations of the NMDA re ceptor complex. The results demonstrate that SPD increases radioligand binding to the PCP receptor through two distinct mechanisms. First, S PD, like glycine, increases the percentage of time that NMDA channels remain in the open state in the presence of L-glutamate, consistent wi th a role as a positive allosteric modulator of NMDA receptor activati on. Second, unlike glycine, SPD increases the affinity of the PCP rece ptor for its ligands. The latter effect does not appear to reflect inc reased NMDA receptor activation. SPD does not induce glycine-like alte ration of the EC(50) value for stimulation of PCP receptor binding by L-glutamate, suggesting that the effects of SPD cannot be attributed s olely to augmentation of glycine binding. These findings demonstrate f irst that total specific PCP receptor binding cannot, of itself, be us ed as an index of NMDA receptor activation and second, glycine and pol yamines differ in the mechanisms by which they potentiate PCP receptor binding.