THE ENDOGENOUS AGONIST QUINOLINIC ACID AND THE NON ENDOGENOUS HOMOQUINOLINIC ACID DISCRIMINATE BETWEEN NMDAR2 RECEPTOR SUBUNITS

Quinolinic acid is an endogenous neurotoxin with NMDA receptor agonist properties. As such it may be the etiologic agent in many diseases. I n this paper the NMDA receptor agonist properties of quinolinic acid, as well as those of homoquinolinic acid, a non endogenous analogue, we re investigated in Xenopus oocytes injected with 12-day-old rat cortic al mRNA or with recombinant NMDA receptors. In oocytes injected with c ortical mRNA, quinolinic acid was a weak NMDA receptor agonist: millim olar concentrations were necessary to induce responses that were small er than maximal responses induced by NMDA; homoquinolinic acid and NMD A had similar affinities but different efficacies :maximal responses i nduced by homoquinolinic acid were larger than maximal responses induc ed by NMDA. Cortical mRNA, as verified by RT-PCR and restriction analy sis, contains various NMDA subunits. In order to investigate if the lo w affinity or efficacy of quinolinic acid could be explained by recept or composition, the pharmacological properties of the putative agonist s were investigated in oocytes expressing binary combinations of recom binant NMDA receptors. Quinolinic acid did not activate receptors cont aining NR1 + NR2C but did activate receptors containing NR1 + NR2A and NR1 + NR2B even if only at millimolar concentrations; homoquinolinic acid activated all subunit combinations but was less efficient than NM DA only in the NR1 + NR2C subunit combination. The relative efficacies of quinolinic acid and homoquinolinic acid were evaluated by comparin g the maximal responses induced by these agonists with those induced b y NMDA and glutamate in the same oocytes. The rank order of potency wa s quinolinic acid < NMDA < homoquinolinic acid less than or equal to g lutamate for the NR1 + NR2A and NR1 + NR2B combinations whereas for NR 1 + NR2C it was quinolinic acid << << homoquinolinic acid < NMDA less than or equal to glutamate. The use of quinolinic acid and homoquinoli nic acid may thus help to identify endogenous receptors containing the NR2C subunit. (C) 1996 Elsevier Science Ltd.