Sensitivity of the N-methyl-D-aspartate receptor channel to butyrophenones is dependent on the ε2 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 epsilon 1/zeta 1, epsilon 2/zeta 1, epsilon 3/zeta 1 and epsilon 4/zeta 1 heteromeric NMDA receptor channels, expressed in Xenopus oocytes. Micromolar concentrations of haloperidol selectively inhibited the epsilon 2/zeta 1 channel, whereas the epsilon 1/zeta 1, epsilon 3/zeta 1 and epsilon 4/zeta 1 channels were enhanced or minimally affected by higher concentrations of haloperidol. Similarly, droperidol and spiperone inhibited the epsilon 2/zeta 1 channel more strongly than the other epsilon/zeta channels, although sensitivities of the epsilon 2/zeta 1 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 epsilon 2 subunit. Furthermore, the replacement with glutamine of the conserved asparagine residue in segment M2, which constitutes the Mg2+ block sites, of the epsilon 2 and zeta 1 subunits (the mutations epsilon 2-N589Q and zeta 1-N598Q, respectively) reduced the sensitivities to haloperidol. The mutation zeta 1-N598Q reduced the sensitivities to haloperidol more effectively than the mutation epsilon 2-N589Q. These results, together with previous findings, suggest that the haloperidol block sites of the NMDA receptor channel partially overlap the Mg2+ block Sites. (C) 1998 Elsevier Science Ltd. All rights reserved.