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. In this paper the NMDA Receptor Agonist properties of quinolinic acid, as well as those of homoquinolinic acid, a non endogenous analogue, were investigated in Xenopus oocytes injected with 12-day-old rat cortical mRNA or with recombinant NMDA receptors. In oocytes injected with cortical mRNA, quinolinic acid was a weak NMDA receptor agonist: millimolar concentrations were necessary to induce responses that were smaller than maximal responses induced by NMDA; homoquinolinic acid and NMDA had similar affinities but different efficacies: maximal responses induced by homoquinolinic acid were larger than maximal responses induced by NMDA. Cortical mRNA, as verified by RT-PCR and restriction analysis, contains various NMDA subunits. In order to investigate if the low affinity or efficacy of quinolinic acid could be explained by receptor composition, the pharmacological properties of the putative agonists were investigated in oocytes expressing binary combinations of recombinant NMDA receptors. Quinolinic acid did not activate receptors containing 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 NMDA only in the NR1 + NR2C subunit combination. The relative efficacies of quinolinic acid and homoquinolinic acid were evaluated by comparing the maximal responses induced by these agonists with those induced by NMDA and glutamate in the same oocytes. The rank order of potency was quinolinic acid < NMDA < homoquinolinic acid < or = glutamate for the NR1 + NR2A and NR1 + NR2B combinations whereas for NR1 + NR2C it was quinolinic acid << << homoquinolinic acid < NMDA < or = glutamate. The use of quinolinic acid and homoquinolinic acid may thus help to identify endogenous receptors containing the NR2C subunit.