DIFFERENT SENSITIVITIES OF NMDA RECEPTOR-CHANNEL SUBTYPES TO NONCOMPETITIVE ANTAGONISTS

FouR kinds of heteromeric N-methyl-D-asparate (NMDA) receptor channels, the epsilon1/zeta1, epsilon2/zeta1, epsilon3/zeta1 and epsilon4/zeta1 channels, were expressed in Xenopus oocytes and their sensitivities to various non-competitive antagonists were examined. The epsilon1/zeta1 and epsilon2/zeta1 channels were more sensitive to (+)MK-801 (dizocilpine) than the epsilon3/zeta1 and epsilon4/zeta1 channels, whereas the sensitivities to phencyclidine (PCP), ketamine and N-allylnormetazocine (SKF-10,047) were only slightly variable among the four epsilon/zeta channels. Furthermore, the replacement by glutamine or arginine of the conserved asparagine residue in segment M2 of the epsilon2 and zeta1 NMDA receptor channel subunits reduced the sensitivities to PCP, ketamine and SKF-10,047, though to different extents. These results, together with previous findings, suggest that these non-competitive antagonists as well as (+)MK-801 and Mg2+ act on a common site.