Sensitivity of the N-methyl-D-aspartate receptor channel to butyrophenones is dependent on the epsilon2 subunit.
The effects of three kinds of butyrophenones, haloperidol, droperidol and spiperone, on the N-methyl-D-aspartate (NMDA) receptor channel were examined on the epsilon1/zeta1, epsilon2/zeta1, epsilon3/zeta1 and epsilon4/zeta1 heteromeric NMDA receptor channels, expressed in Xenopus oocytes. Micromolar concentrations of haloperidol selectively inhibited the epsilon2/zeta1 channel, whereas the epsilon1/zeta1, epsilon3/zeta1 and epsilon4/zeta1 channels were enhanced or minimally affected by higher concentrations of haloperidol. Similarly, droperidol and spiperone inhibited the epsilon2/zeta1 channel more strongly than the other epsilon/zeta channels, although sensitivities of the epsilon2/zeta1 channel to droperidol and spiperone were lower than those to haloperidol. These results suggest that the sensitivities of the NMDA receptor channels to butyrophenones are dependent on the epsilon2 subunit. Furthermore, the replacement with glutamine of the conserved asparagine residue in segment M2, which constitutes the Mg2+ block sites, of the epsilon2 and zeta1 subunits (the mutations epsilon2-N589Q and zeta1-N598Q, respectively) reduced the sensitivities to haloperidol. The mutation zeta1-N598Q reduced the sensitivities to haloperidol more effectively than the mutation epsilon2-N589Q. These results, together with previous findings, suggest that the haloperidol block sites of the NMDA receptor channel partially overlap the Mg2+ block sites.
Yamakura
T
T
Department of Anesthesiology, Niigata University School of Medicine, Asahimachi, Japan. yamakura@med.niigata-u.ac.jp
Sakimura
K
K
Mishina
M
M
Shimoji
K
K
D019943:Amino Acid Substitution; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002090:Butyrophenones / Q000494:pharmacology*; D004329:Droperidol / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013134:Spiperone / Q000494:pharmacology; D014982:Xenopus laevis
D014150:Antipsychotic Agents; D002090:Butyrophenones; D016194:Receptors, N-Methyl-D-Aspartate; D013134:Spiperone; D008274:Magnesium; D006220:Haloperidol; D004329:Droperidol