INFLUENCE OF EXTRACELLULAR PH ON INHIBITION BY IFENPRODIL AT N-METHYL-D-ASPARTATE RECEPTORS IN XENOPUS OOCYTES

Ifenprodil is an atypical N-methyl-D-aspartate (NMDA) receptor antagon ist that selectively blocks receptors containing the NR2B subunit. It has been proposed that ifenprodil may act at a stimulatory polyamine s ite on NMDA receptors, although interactions between ifenprodil and po lyamines are non-competitive. NMDA receptors are also inhibited by ext racellular protons, and an interaction between protons and polyamine s timulation has been described. Using voltage-clamp recording of recomb inant NR1/NR2B receptors expressed in oocytes, ifenprodil inhibition w as found to be pH sensitive with a smaller inhibition at alkaline pH. Similar effects of pH were seen on inhibition by nylidrin, eliprodil, and haloperidol, which are thought to act at the ifenprodil binding si te. The pH sensitivity of ifenprodil block occurs at NR1B/NR2B as well as NR1A/NR2B receptors, suggesting that it is not influenced by the e xon-5 insert that is present in NR1B but absent in NR1A. Protons may d irectly affect the ifenprodil binding site or may alter the coupling o f ifenprodil binding to inhibition of channel gating. (C) 1997 Elsevie r Science Ireland Ltd.