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.
Rodríguez-Paz
J M
JM
Department of Anesthesiology, University of Massachusetts Medical Center, Worcester 01655, USA.
Anantharam
V
V
Treistman
S N
SN
D017398:Alternative Splicing; D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D005998:Glycine / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D007700:Kinetics; D016202:N-Methylaspartate / Q000494:pharmacology*; D009865:Oocytes; D012333:RNA, Messenger / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D014981:Xenopus
D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D007649:Ketamine; D016291:Dizocilpine Maleate; D005998:Glycine