PHARMACOLOGICAL CHARACTERIZATION OF HETERODIMERIC NMDA RECEPTORS COMPOSED OF NR 1A AND 2B SUBUNITS - DIFFERENCES WITH RECEPTORS FORMED FROMNR 1A AND 2A

Pharmacological and molecular biological evidence indicates the existe nce of multiple types of NMDA receptors within the CNS. We have charac terized pharmacological properties of receptors assembled from the com bination of NR 1a and NR 2B subunits (NR 1a/2B) expressed in transfect ed cells using both I-125-MK-801 binding assays and electrophysiologic al measures. Binding of I-125-MK-801 to cells transfected with NR 1a/2 B is saturable with a K-D of 440 pM. The binding is potently inhibited by ketamine, dextromethorphan, phencyclidine, and MK-801 and is stimu lated by low concentrations of magnesium. These properties resemble th ose of native receptors and receptors produced by NR 1a/2A. However, I -125-MK-801 binding to membranes from cells transfected with NR 1a/2B is inhibited with high affinity by ifenprodil and is stimulated by spe rmidine, unlike receptors assembled from NR 1a/2A. NMDA-induced curren ts measured in cells transfected with either NR 1a/2A or NR 1a/2B have pharmacological properties that correlate well with the binding studi es. Currents in cells transfected with NR 1a/2B are potentiated by spe rmidine and blocked with high affinity by ifenprodil, whereas currents in cells transfected with NR 1a/2A are not enhanced by spermidine and are weakly inhibited by ifenprodil. These data suggest that pharmacol ogical heterogeneity in native NMDA receptors may be explained by comb inations of different subunits.