AN NR2B POINT MUTATION AFFECTING HALOPERIDOL AND CP101,606 SENSITIVITY OF SINGLE RECOMBINANT N-METHYL-D-ASPARTATE RECEPTORS

Haloperidol and ifenprodil are N-methyl-D-aspartate (NMDA) receptor (N R) antagonists with preference for the NR1/NR2B subunit combination. P revious investigations utilizing I-125- MK801 binding assays with reco mbinant receptors distinguished certain structural determinants on the NR2B subunit for these two drugs, with glutamate 201 being critical f or haloperidol sensitivity and arginine 337 being important for ifenpr odil block. Other studies, however, suggested that these two sites pha rmacologically overlap. In an attempt to resolve these discrepancies, we have characterized the actions of haloperidol and CP101,606, an ife nprodil analog, on the single-channel properties of NR1/NR2B(E201R rec eptors transiently expressed in Chinese hamster ovary cells, because r eceptors formed by NR1/NR2B(R337K) appear to be nonfunctional. Haloper idol (10 mu M) inhibited wild-type NR1/NR2B channels by decreasing the frequency of channel opening, whereas CP101,606 (0.5 mu M) antagonize d NR1/NR2B channel activity by decreasing both the open dwell time and the frequency of channel opening. The inhibitory actions of both drug s were virtually absent in the mutant NR1/NR2B(E201R) receptors. These results suggest that glutamate 201 is critical for both haloperidol a nd CP101,606 inhibition, thus demonstrating common features in the act ion of these two antagonists.