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Glycine regulation of the N-methyl-D-aspartate receptor-gated ion channel in hippocampal membranes.
Mol Pharmacol. 1989 Aug; 36(2):273-9.MP

Abstract

The N-methyl-D-aspartate receptor-gated ion channel (NMDA channel) is regulated by glycine. To examine the interaction of glycine and NMDA receptor ligands on NMDA channel function, we used a biochemical marker of channel opening, [3H]N-(1-[thienyl]cyclohexyl)piperidine (TCP). We quantified [3H]glycine,L-[3H]glutamate, and TCP binding in an identical membrane preparation. This allowed direct comparison of NMDA and glycine receptor occupancy and channel activation. Glycine increased the association and dissociation rates of NMDA-dependent TCP binding to hippocampal membranes, without altering the Kd or Bmax for TCP binding. Structurally similar amino acids mimicked the action of glycine, with D-isomers being more potent than L-isomers. The potency of glycine in regulating TCP binding matched that for displacing [3H]glycine. Glycine stimulation of TCP binding required the presence of NMDA agonists and was inhibited by the NMDA antagonist D-2-amino-5-phosphonovaleric acid. Glycine stimulation of NMDA-dependent TCP binding was not associated with an increase in agonist binding to the NMDA receptor. Likewise, NMDA stimulation of glycine-dependent TCP binding was not associated with an increase in the binding of glycine to the glycine receptor. These findings permit the following conclusions: 1) glycine stimulates TCP binding solely by increasing the access of TCP to its site in the NMDA channel; 2) TCP binding can be used to quantify glycine regulation of the NMDA channel; 3) a stereospecific glycine receptor, as part of the NMDA receptor-channel complex, regulates NMDA-evoked channel opening by a mechanism not involving increased agonist binding to the NMDA receptor. Thus, it appears that the mechanism of glycine and NMDA receptor regulation of the NMDA channel is analogous to that of a two-key lock; both receptors, by independent and mutually required mechanisms, alter channel conformation to allow ion passage.

Authors+Show Affiliations

Department of Medicine (Neurology), Duke University Medical Center, Durham, North Carolina.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

2475759

Citation

Bonhaus, D W., et al. "Glycine Regulation of the N-methyl-D-aspartate Receptor-gated Ion Channel in Hippocampal Membranes." Molecular Pharmacology, vol. 36, no. 2, 1989, pp. 273-9.
Bonhaus DW, Yeh GC, Skaryak L, et al. Glycine regulation of the N-methyl-D-aspartate receptor-gated ion channel in hippocampal membranes. Mol Pharmacol. 1989;36(2):273-9.
Bonhaus, D. W., Yeh, G. C., Skaryak, L., & McNamara, J. O. (1989). Glycine regulation of the N-methyl-D-aspartate receptor-gated ion channel in hippocampal membranes. Molecular Pharmacology, 36(2), 273-9.
Bonhaus DW, et al. Glycine Regulation of the N-methyl-D-aspartate Receptor-gated Ion Channel in Hippocampal Membranes. Mol Pharmacol. 1989;36(2):273-9. PubMed PMID: 2475759.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glycine regulation of the N-methyl-D-aspartate receptor-gated ion channel in hippocampal membranes. AU - Bonhaus,D W, AU - Yeh,G C, AU - Skaryak,L, AU - McNamara,J O, PY - 1989/8/1/pubmed PY - 1989/8/1/medline PY - 1989/8/1/entrez SP - 273 EP - 9 JF - Molecular pharmacology JO - Mol Pharmacol VL - 36 IS - 2 N2 - The N-methyl-D-aspartate receptor-gated ion channel (NMDA channel) is regulated by glycine. To examine the interaction of glycine and NMDA receptor ligands on NMDA channel function, we used a biochemical marker of channel opening, [3H]N-(1-[thienyl]cyclohexyl)piperidine (TCP). We quantified [3H]glycine,L-[3H]glutamate, and TCP binding in an identical membrane preparation. This allowed direct comparison of NMDA and glycine receptor occupancy and channel activation. Glycine increased the association and dissociation rates of NMDA-dependent TCP binding to hippocampal membranes, without altering the Kd or Bmax for TCP binding. Structurally similar amino acids mimicked the action of glycine, with D-isomers being more potent than L-isomers. The potency of glycine in regulating TCP binding matched that for displacing [3H]glycine. Glycine stimulation of TCP binding required the presence of NMDA agonists and was inhibited by the NMDA antagonist D-2-amino-5-phosphonovaleric acid. Glycine stimulation of NMDA-dependent TCP binding was not associated with an increase in agonist binding to the NMDA receptor. Likewise, NMDA stimulation of glycine-dependent TCP binding was not associated with an increase in the binding of glycine to the glycine receptor. These findings permit the following conclusions: 1) glycine stimulates TCP binding solely by increasing the access of TCP to its site in the NMDA channel; 2) TCP binding can be used to quantify glycine regulation of the NMDA channel; 3) a stereospecific glycine receptor, as part of the NMDA receptor-channel complex, regulates NMDA-evoked channel opening by a mechanism not involving increased agonist binding to the NMDA receptor. Thus, it appears that the mechanism of glycine and NMDA receptor regulation of the NMDA channel is analogous to that of a two-key lock; both receptors, by independent and mutually required mechanisms, alter channel conformation to allow ion passage. SN - 0026-895X UR - https://www.unboundmedicine.com/medline/citation/2475759/Glycine_regulation_of_the_N_methyl_D_aspartate_receptor_gated_ion_channel_in_hippocampal_membranes_ DB - PRIME DP - Unbound Medicine ER -