The PCP Site of the NMDA Receptor Complex

Abstract

Electropharmacological experiments by Lodge and his co-workers (Anis et al., 1983) first demonstrated that dissociative anaesthetics such as PCP and ketamine selectively block responses evoked by applications of NMDA agonists while sparing those mediated by other subtypes of excitatory amino acid receptors. Since that time others including ourselves demonstrated, using patch and voltage-clamp techniques, that this blockade is both dependent upon the membrane potential (voltage-dependent) and the presence of activated receptors (usedependent) (Honey et al., 1985; Huettner and Bean, 1987; Kemp et al., 1987;.Kushner et al., 1988; MacDonald et al., 1987; Mayer et al., 1988; Rothman, 1988). These are characteristics which have most often been ascribed to an action of antagonists on voltage-dependent channels or on the channel domains of ligand-activated channels (see Hille, 1984). For the PCP site, a variety of binding studies have also shown that it is most likely located on or near the NMDA channel (Kemp et al., 1987; Monaghan et al., 1989). This site is most accessible when the receptor is in an activated state implying that the apparent affinity of PCP for its site is determined by channel gating. Nevertheless, much of this evidence is circumstantial and open to various interpretations.