THE GLYCINE COAGONIST SITE OF THE NMDA RECEPTOR Raymond Dingledine, Nancy W. Kleckner and Christopher J. McBain Department of Pharmacology University of North Carolina School of Medicine Chapel Hill, NC 27599 USA INTRODUCTION The discovery of the glycine binding site on the NMDA receptor (Johnson and Ascher, 1987) is recognized as a highly significa;1t event by those interested in receptor-channel mechanisms. It also offers a new target site in drug development for the treatment of neuropa-thologies associated with NMDA receptor activation. The list of neural dysfunctions mediated in part by synaptic activation of NMDA receptors very likely includes epileptiform seizures (Croucher et ai., 1982) and brain damage induced by ischemia or hypoxia in some models (Simon et ai., 1984). Growing evidence indicates however that NMDA receptor activation is important also for establishing certain neuronal connections during development (Tsumoto et ai., 1987; Kleinschmidt et ai., 1987; Lincoln et ai., 1988) and has been implicated in some types of learning or memory (Morris et ai., 1986). Thus both agonists and antagonists of the NMDA receptor may find clinical utility in the future. Currently available NMDA receptor blockers, acting either at the glutamate binding site or the open ion channel, either have difficulty penetrating the blood-brain barrier or have unacceptable side effects such as psychosis. The glycine site appears to present a pharmacology sufficiently different from that of the other binding sites on the NMDA receptor to offer a novel target for new drug discovery. The preparation we hilve used is the Xenopus oocyte injected with rat brain mRNA. It is a large (1 mm diameter), hardy cell that ciln be cultured easily for a week or more after injection, during which time transliltion of the foreign mRNA, ilssembly of multisubunit recep-tors and right-side-out insertion into the plasma membrane occurs. Receptor properties arc then studied under well-defined voltage cl<Jmp conditions. The reproducibility of this preparation offers a reliable bioassilY for the quantitiltive study of receptor-coupled ion channel properties. We have shown previously that NMDA and kainilte/quisqualate receptors with properties indistin- guishable from those in neurons are expressed by oocytes (Verdoom et ai., 1987, 1989; Verdoorn and Dingledine, 1988). Here we summarize some of our recent work on the pharmaco-Iogical characteri- zation of the glycine binding site on NMDA receptors (Kleckner and Dingledine, 1988, 1989; McBain et ai., 1989). EXCilUlory Ammo ACids and Neuronal P/asllclIV Edlled by Y. Ben·An . Plenum Press, New York, 1990 '7