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Cloning and functional characterization of human heteromeric N-methyl-D-aspartate receptors.
J Pharmacol Exp Ther. 1996 Aug; 278(2):808-16.JP

Abstract

Human cDNAs encoding N-methyl-D-aspartate receptor type (NMDAR)1A, NMDAR2A and NMDAR2B subunits were cloned and receptors encoded by these cDNAs were functionally expressed by injection of the respective mRNAs in Xenopus oocytes. The pharmacological properties of recombinant human N-methyl-D-aspartate (NMDA) receptors were characterized by profiling two agonists and four antagonists at both the NMDA and glycine sites in voltage-clamped oocytes. NMDA, glycine and D-serine were significantly more potent at human NMDAR (hNMDAR)1A/2B receptors than at nNMDAR1A/2A, whereas there was no detectable subtype-dependent difference in the potency of glutamate. Of the NMDA-site antagonists tested, CGP 43487 and 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonate exhibited 5.8- and 3.9-fold greater potency, respectively, at hNMDAR1A/2A receptors than at hNMDAR1A/2B. Of the four glycine-site competitive antagonists tested, L-689,560 displayed 5-fold greater potency at hNMDAR1A/2A, whereas 5,7-dichlorokynurenic acid, HA-966 and CGP 58411 did not discriminate between hNMDAR1A/2A and hNMDAR1A/2B. Receptors resulting from injection of hNMDAR1A, hNMDAR2A and hNMDAR2B transcripts in a 1:1:1 ratio were indistinguishable from hNMDAR1A/2B receptors in terms of their sensitivity to NMDA, glycine, D-serine, CGS 19755 and CGP 40116. Ifenprodil was approximately 350-fold more potent at hNMDAR1A/2B than at hNMDAR1A/2A receptors. Ifenprodil sensitivities of receptors formed in oocytes injected with a constant amount of hNMDAR1A mRNA but varying ratios of hNMDAR2A or hNMDAR2B mRNAs were compared. The receptors expressed at a 10:1 ratio of 2A:2B transcripts displayed an ifenprodil sensitivity that would be predicted for a population in which 51% was represented by hNMDAR(1A)2(2A)3 complexes. Our results underscore the need for subtype-selective compounds acting at novel sites to sufficiently probe the pharmacological differences between NMDA receptor subtypes formed by different subunit combinations.

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Authors+Show Affiliations

Hess SD
SIBIA Neurosciences, Inc., La Jolla, California, USA.
Daggett LP
No affiliation info available
Crona J
No affiliation info available
Deal C
No affiliation info available
Lu CC
No affiliation info available
Urrutia A
No affiliation info available
Chavez-Noriega L
No affiliation info available
Ellis SB
No affiliation info available
Johnson EC
No affiliation info available
Veliçelebi G
No affiliation info available

MeSH

AnimalsDNA, ComplementaryDose-Response Relationship, DrugExcitatory Amino Acid AntagonistsGlutamic AcidHumansN-MethylaspartatePiperidinesReceptors, N-Methyl-D-AspartateXenopus

Pub Type(s)

Journal Article

Language

eng

PubMed ID

8768735

Citation

Hess, S D., et al. "Cloning and Functional Characterization of Human Heteromeric N-methyl-D-aspartate Receptors." The Journal of Pharmacology and Experimental Therapeutics, vol. 278, no. 2, 1996, pp. 808-16.
Hess SD, Daggett LP, Crona J, et al. Cloning and functional characterization of human heteromeric N-methyl-D-aspartate receptors. J Pharmacol Exp Ther. 1996;278(2):808-16.
Hess, S. D., Daggett, L. P., Crona, J., Deal, C., Lu, C. C., Urrutia, A., Chavez-Noriega, L., Ellis, S. B., Johnson, E. C., & Veliçelebi, G. (1996). Cloning and functional characterization of human heteromeric N-methyl-D-aspartate receptors. The Journal of Pharmacology and Experimental Therapeutics, 278(2), 808-16.
Hess SD, et al. Cloning and Functional Characterization of Human Heteromeric N-methyl-D-aspartate Receptors. J Pharmacol Exp Ther. 1996;278(2):808-16. PubMed PMID: 8768735.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cloning and functional characterization of human heteromeric N-methyl-D-aspartate receptors. AU - Hess,S D, AU - Daggett,L P, AU - Crona,J, AU - Deal,C, AU - Lu,C C, AU - Urrutia,A, AU - Chavez-Noriega,L, AU - Ellis,S B, AU - Johnson,E C, AU - Veliçelebi,G, PY - 1996/8/1/pubmed PY - 1996/8/1/medline PY - 1996/8/1/entrez SP - 808 EP - 16 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 278 IS - 2 N2 - Human cDNAs encoding N-methyl-D-aspartate receptor type (NMDAR)1A, NMDAR2A and NMDAR2B subunits were cloned and receptors encoded by these cDNAs were functionally expressed by injection of the respective mRNAs in Xenopus oocytes. The pharmacological properties of recombinant human N-methyl-D-aspartate (NMDA) receptors were characterized by profiling two agonists and four antagonists at both the NMDA and glycine sites in voltage-clamped oocytes. NMDA, glycine and D-serine were significantly more potent at human NMDAR (hNMDAR)1A/2B receptors than at nNMDAR1A/2A, whereas there was no detectable subtype-dependent difference in the potency of glutamate. Of the NMDA-site antagonists tested, CGP 43487 and 3-(2-carboxypiperazin-4-yl) propyl-1-phosphonate exhibited 5.8- and 3.9-fold greater potency, respectively, at hNMDAR1A/2A receptors than at hNMDAR1A/2B. Of the four glycine-site competitive antagonists tested, L-689,560 displayed 5-fold greater potency at hNMDAR1A/2A, whereas 5,7-dichlorokynurenic acid, HA-966 and CGP 58411 did not discriminate between hNMDAR1A/2A and hNMDAR1A/2B. Receptors resulting from injection of hNMDAR1A, hNMDAR2A and hNMDAR2B transcripts in a 1:1:1 ratio were indistinguishable from hNMDAR1A/2B receptors in terms of their sensitivity to NMDA, glycine, D-serine, CGS 19755 and CGP 40116. Ifenprodil was approximately 350-fold more potent at hNMDAR1A/2B than at hNMDAR1A/2A receptors. Ifenprodil sensitivities of receptors formed in oocytes injected with a constant amount of hNMDAR1A mRNA but varying ratios of hNMDAR2A or hNMDAR2B mRNAs were compared. The receptors expressed at a 10:1 ratio of 2A:2B transcripts displayed an ifenprodil sensitivity that would be predicted for a population in which 51% was represented by hNMDAR(1A)2(2A)3 complexes. Our results underscore the need for subtype-selective compounds acting at novel sites to sufficiently probe the pharmacological differences between NMDA receptor subtypes formed by different subunit combinations. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/8768735/Cloning_and_functional_characterization_of_human_heteromeric_N_methyl_D_aspartate_receptors_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8768735 DB - PRIME DP - Unbound Medicine ER -