BLOCK OF THE N-METHYL-D-ASPARTATE RECEPTOR BY PHENCYCLIDINE-LIKE DRUGS IS INFLUENCED BY ALTERNATIVE SPLICING

N-Methyl-D-aspartate (NMDA) receptors were expressed in Xenopus oocytes from injected mRNA. The presence of an alternatively-spliced insertion encoding 21 amino acids at the N-terminus of the NMDAR1 (NR1(111)) subunit, made homomeric assemblies of the receptor more sensitive to ketamine and MK-801 than receptors assembled from NMDAR1 subunits lacking this insert (NR1(011) and NR1(001)). The influence of this insert was maintained when NR1 subunits were co-expressed in heteromeric combinations with NR2B. The increased sensitivity of the receptors containing the insert (NR1(111)) was accompanied by a faster on-rate for drug action than was observed for receptors lacking the insert (NR1(011) and NR1(001)). Our results suggest that the action of phencyclidine-like drugs is influenced by the presence of Insertion I in the NMDA isoforms, generated by alternative splicing.