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N-methyl-D-aspartate/glycine and quisqualate/kainate receptors expressed in Xenopus oocytes: antagonist pharmacology.
Mol Pharmacol. 1989 Mar; 35(3):360-8.MP

Abstract

Quantitative pharmacological studies were done to determine the properties of excitatory amino acid receptors expressed in Xenopus oocytes injected with rat brain mRNA. Smooth currents with properties indicative of N-methyl-D-aspartate (NMDA) and quisqualate/kainate receptors were observed in mRNA-injected oocytes. Schild analysis of currents evoked by NMDA indicated that the EAA receptor antagonist D-2-amino-5-phosphonovalerate (D-APV) exerted a competitive block of the oocyte NMDA receptor, because the Schild regression was linear with a slope not significantly different from unity (1.03 +/- 0.025) up to 100 microM D-APV. The pA2 estimated for D-APV antagonism of NMDA currents (5.87 +/- 0.043) was nearly identical to that for D-APV as an L-aspartate antagonist (pA2 = 5.86 +/- 0.073, slope = 0.97 +/- 0.036), suggesting that these two agonists are selective for NMDA receptors in oocytes up to concentrations well above 1 mM. 6-Nitro-7-cyano-quinoxaline-2,3-dione (CNQX) reduced the maximum NMDA response significantly (70% reduction by 15 microM CNQX) but had no effect on the NMDA EC50. CNQX exerted a mixed competitive-noncompetitive block of the glycine site on NMDA receptors; 15 microM CNQX increased the glycine EC50 by 5-fold and reduced the maximum glycine response by 35%. In addition, CNQX exerted a potent and competitive antagonism of currents evoked by kainate. The Schild regression was linear up to 30 microM CNQX with a slope of 1.02 +/- 0.014 and a pA2 of 6.53 +/- 0.029. The block of kainate or NMDA currents by 2 microM CNQX was not voltage dependent. D-APV exerted a weak antagonism of kainate-evoked currents, with a pA2 of 3.39 +/- 0.044, but the slope of the Schild regression was slightly less than 1 (0.90 +/- 0.03). These data demonstrate a clear pharmacological distinction between receptors that mediate the kainate- and NMDA-induced currents and quantify the potency of CNQX and D-APV acting at NMDA/glycine and quisqualate/kainate receptors. The implications of these data for the identification of EAA receptors in oocytes and the classification of neuronal EAA receptors are discussed.

Authors+Show Affiliations

Department of Pharmacology, University of North Carolina, Chapel Hill 27599.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

2564633

Citation

Verdoorn, T A., et al. "N-methyl-D-aspartate/glycine and Quisqualate/kainate Receptors Expressed in Xenopus Oocytes: Antagonist Pharmacology." Molecular Pharmacology, vol. 35, no. 3, 1989, pp. 360-8.
Verdoorn TA, Kleckner NW, Dingledine R. N-methyl-D-aspartate/glycine and quisqualate/kainate receptors expressed in Xenopus oocytes: antagonist pharmacology. Mol Pharmacol. 1989;35(3):360-8.
Verdoorn, T. A., Kleckner, N. W., & Dingledine, R. (1989). N-methyl-D-aspartate/glycine and quisqualate/kainate receptors expressed in Xenopus oocytes: antagonist pharmacology. Molecular Pharmacology, 35(3), 360-8.
Verdoorn TA, Kleckner NW, Dingledine R. N-methyl-D-aspartate/glycine and Quisqualate/kainate Receptors Expressed in Xenopus Oocytes: Antagonist Pharmacology. Mol Pharmacol. 1989;35(3):360-8. PubMed PMID: 2564633.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - N-methyl-D-aspartate/glycine and quisqualate/kainate receptors expressed in Xenopus oocytes: antagonist pharmacology. AU - Verdoorn,T A, AU - Kleckner,N W, AU - Dingledine,R, PY - 1989/3/1/pubmed PY - 1989/3/1/medline PY - 1989/3/1/entrez SP - 360 EP - 8 JF - Molecular pharmacology JO - Mol Pharmacol VL - 35 IS - 3 N2 - Quantitative pharmacological studies were done to determine the properties of excitatory amino acid receptors expressed in Xenopus oocytes injected with rat brain mRNA. Smooth currents with properties indicative of N-methyl-D-aspartate (NMDA) and quisqualate/kainate receptors were observed in mRNA-injected oocytes. Schild analysis of currents evoked by NMDA indicated that the EAA receptor antagonist D-2-amino-5-phosphonovalerate (D-APV) exerted a competitive block of the oocyte NMDA receptor, because the Schild regression was linear with a slope not significantly different from unity (1.03 +/- 0.025) up to 100 microM D-APV. The pA2 estimated for D-APV antagonism of NMDA currents (5.87 +/- 0.043) was nearly identical to that for D-APV as an L-aspartate antagonist (pA2 = 5.86 +/- 0.073, slope = 0.97 +/- 0.036), suggesting that these two agonists are selective for NMDA receptors in oocytes up to concentrations well above 1 mM. 6-Nitro-7-cyano-quinoxaline-2,3-dione (CNQX) reduced the maximum NMDA response significantly (70% reduction by 15 microM CNQX) but had no effect on the NMDA EC50. CNQX exerted a mixed competitive-noncompetitive block of the glycine site on NMDA receptors; 15 microM CNQX increased the glycine EC50 by 5-fold and reduced the maximum glycine response by 35%. In addition, CNQX exerted a potent and competitive antagonism of currents evoked by kainate. The Schild regression was linear up to 30 microM CNQX with a slope of 1.02 +/- 0.014 and a pA2 of 6.53 +/- 0.029. The block of kainate or NMDA currents by 2 microM CNQX was not voltage dependent. D-APV exerted a weak antagonism of kainate-evoked currents, with a pA2 of 3.39 +/- 0.044, but the slope of the Schild regression was slightly less than 1 (0.90 +/- 0.03). These data demonstrate a clear pharmacological distinction between receptors that mediate the kainate- and NMDA-induced currents and quantify the potency of CNQX and D-APV acting at NMDA/glycine and quisqualate/kainate receptors. The implications of these data for the identification of EAA receptors in oocytes and the classification of neuronal EAA receptors are discussed. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/2564633/N_methyl_D_aspartate/glycine_and_quisqualate/kainate_receptors_expressed_in_Xenopus_oocytes:_antagonist_pharmacology_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=2564633 DB - PRIME DP - Unbound Medicine ER -