To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KER:229
Binding of antagonist, NMDA receptors leads to Inhibition, NMDARs
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development induces impairment of learning and memory abilities||adjacent||High||Agnes Aggy (send email)||Open for citation & comment||TFHA/WNT Endorsed|
|Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging||adjacent||High||Arthur Author (send email)||Open for citation & comment||TFHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
It is well documented that prolonged/chronic antagonism of NMDARs triggers the downstream KE named inhibition of NMDARs. Shorter term binding to the same receptors may trigger different downstream KEs, such as up-regulation of the NMDARs, resulting in toxic increased influx of calcium and to cell death. Consequently, this information can be captured in other KERs and AOP.
Evidence Supporting this KER
There is structural mechanistic understanding supporting the relationship between MIE (NMDARs, binding of antagonists) and KE (NMDARs, inhibition). Crystal structure studies are used to study the binding of antagonists/agonists to NMDA receptors. In case of NMDAR antagonists, the binding to the receptor causes LBD conformation changes which promote channel closure leading to reduced Ca+2 influx (Blanke and VanDongen, 2009). This lack of measurable ion flux is applied as an indication of NMDAR inhibition.
Uncertainties and Inconsistencies
Pb2+ has been found to produce either potentiation or inhibition depending on: a) the subunit composition of NMDA receptors, b) endogenous glutamate concentration and c) Pb2+ dosage. In case that the NMDA receptors are saturated by agonist, Pb2+ at low concentrations (<1 µM) acts as a positive modulator of agonist action at NR1b-2AC and NR1a-2AB subunit complexes, whereas at higher concentrations, Pb2+ it behaves as a potent inhibitor of all recombinant NMDA receptors tested and was least potent at NR1b-2AC (Omelchenko et al., 1996; 1997), meaning that Pb2+ is not always acting as NMDAR inhibitor but it can also behave as NMDAR activator under certain conditions.
As an alternative mechanism of toxicity, Pb was shown to cause oxidative stress. In addition, it has the ability to substitute other bivalent cations like Ca2+,Mg2+, Fe2+ and monovalent cations like Na+ (for review, see Flora et al., 2012)
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The biophysical properties of rat and human receptors have been mostly assessed through recombinant studies, whereas the pharmacological properties of rat and human NMDA receptors have not been fully explored and compared yet (Hedegaard et al., 2012). Mean channel open times for human NMDA receptor subtypes in recombinant protein studies are similar to those of the corresponding rat NMDA receptor subtypes. However, mean single-channel conductances for human NMDA receptor subtypes appear lower than those of the corresponding rat NMDA receptor subtypes. Regarding pharmacological properties of the receptors, the differences were less than 2-fold and were not observed at the same subtypes for all the antagonists tested, suggesting that the molecular pharmacology of NMDA receptor is conserved between human and rat, although some inter-species differences are seen in IC50 values using two-electrode voltage-clamp recordings (Hedegaard et al., 2012),
Alkondon M, Costa AC, Radhakrishnan V, Aronstam RS, Albuquerque EX. (1990) Selective blockade of NMDA-activated channel currents may be implicated in learning deficits caused by lead. FEBS Lett. 261: 124-130.
Blanke ML, VanDongen AMJ. (2009) Activation Mechanisms of the NMDA Receptor. In: Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press; Chapter 13. Available from: http://www.ncbi.nlm.nih.gov/books/NBK5274/
de Marchena J, Roberts AC, Middlebrooks PG, Valakh V, Yashiro K, Wilfley LR, Philpot BD. (2008) NMDA receptor antagonists reveal age-dependent differences in the properties of visual cortical plasticity. J Neurophysiol. 100: 1936-1948.
Flora G, Gupta D, Tiwari A. 2012. Toxicity of lead: A review with recent updates. Interdisciplinary toxicology 5(2): 47-58.
Gavazzo P, Gazzoli A, Mazzolini M, Marchetti C. (2001) Lead inhibition of NMDA channels in native and recombinant receptors. NeuroReport. 12: 3121-3125.
Gavazzo P, Zanardi I, Baranowska-Bosiacka I, Marchetti C. (2008) Molecular determinants of Pb2+ interaction with NMDA receptor channels. Neurochem Int. 52: 329-337.
Guilarte TR, Miceli RC. (1992) Age-dependent effects of lead on [3H]-MK-801 binding to the NMDA receptor-gated ionophore: In vitro and in vivo studies. Neurosci Lett. 148: 27-30.
Guilarte TR. (1997) Pb2+ Inhibits Nmda Receptor Function at High and Low Affinity Sites: Developmental and Regional Brain Expression. Neurotoxicology 18: 43-51.
Guilarte TR, McGlothan JL. (1998) Hippocampal NMDA Receptor mRNA Undergoes Subunit Specific Changes During Developmental Lead Exposure. Brain Res. 790: 98-107.
Hedegaard MK, Hansen KB, Andersen KT, Bräuner-Osborne H, Traynelis SF. (2012) Molecular pharmacology of human NMDA receptors. Neurochem Int. 61: 601-609.
Lasley SM, Gilbert ME. (1999) Lead inhibits the rat N-methyl-d-aspartate receptor channel by binding to a site distinct from the zinc allosteric site. Toxicol Appl Pharmacol. 159: 224-233.
MacDonald JF, Jackson MF, Beazely MA. (2006) Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors. Crit Rev Neurobiol. 18: 71-84.
Neal AP, Worley PF, Guilarte TR. (2011) Lead exposure during synaptogenesis alters NMDA receptor targeting via NMDA receptor inhibition. Neurotoxicology 32: 281-289.
Nihei MK, Guilarte TR. (1999) NMDAR-2A subunit protein expression is reduced in the hippocampus of rats exposed to Pb2+ during development. Brain Res Mol Brain Res. 66: 42-49.
Omelchenko IA, Nelson CS, Marino JL., Allen CN. (1996). The sensitivity of N-methyl-d-aspartate receptors to lead inhibition is dependent on the receptor subunit composition. J Pharmacol Exp Ther. 278: 15-20.
Omelchenko IA, Nelson CS, Allen CN. (1997) Lead inhibition of N-Methyl-D-aspartate receptors containing NR2A, NR2C and NR2D subunits. J Pharmacol Exp Ther. 282: 1458-1464.
Rumbaugh G, Vicini S. (1999) Distinct Synaptic and Extrasynaptic NMDA Receptors in Developing Cerebellar Granule Neurons. J Neurosc. 19: 10603-10610.
Traynelis S, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. (2010) Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 62: 405-496.
Zhang XY, Liu AP, Ruan DY, Liu J. (2002) Effect of developmental lead exposure on the expression of specific NMDA receptor subunit mRNAs in the hippocampus of neonatal rats by digoxigenin-labeled in situ hybridization histochemistry. Neurotox Teratol 24: 149-160.