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Inhibition, NMDARs leads to Decreased, Calcium influx
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||Moderate||Anna Price (send email)||Open for citation & comment||WPHA/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||Moderate||Florianne Tschudi-Monnet (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
The NMDA receptor is distinct in two ways: firstly, it is both ligand-gated and voltage-dependent and secondly, it requires co-activation by two ligands: glutamate and either D-serine or glycine.
NMDA receptor activation allows the influx of Ca2+ only when the receptor is occupied by L-glutamate or other agonists (and removal of Mg++ block) resulting in the postsynaptic membrane depolarization. In contrast, binding of antagonist to NMDA receptor decreases or eliminates Ca2+ influx and consequently dramatically decreases intracellular influx of Ca2+ levels (reviewed in Higley and Sabatini, 2012).
Evidence Collection Strategy
Evidence Supporting this KER
The relationship between KE (NMDARs, Inhibition) and KE (Calcium influx, Decreased) is plausible as the function evaluation of NMDA receptors is commonly carried out by measurement of intracellular influx of Ca2+ upon NMDA receptor stimulation by agonist. Calcium imaging techniques have been extensively utilized to investigate the relationship between these two KEs. Almost 15% of the current through NMDA receptors is mediated by Ca2+ under physiological conditions (Higley and Sabatini, 2012).
It has been shown that less than five and, occasionally only a single NMDA receptor opens under physiological conditions, causing a total Ca2+ influx of about 6000 ions into a dendritic spine head reaching a concentration of ∼10 µM (Higley and Sabatini, 2012). However, the majority of the ions are rapidly eliminated by binding Ca2+ proteins, reaching ∼1 µM of free Ca2+ concentration (Higley and Sabatini, 2012).
In rat primary forebrain cultures, the intracellular Ca2+ increases after activation of the NMDA receptor and this increase is blocked when the cells are cultured under Ca2+ free conditions, demonstrating that the NMDA-evoked increase in intracellular Ca2+ derives from extracellular and not intracellular sources (Liu et al., 2013).
Neurons in brain slices from wild-type (GluRε2+/+) mice showed increase of intracellular Ca2+ in the presence of 100 μM NMDA that was completely inhibited after exposure to 100 mM APV. In contrast, the NMDA-mediated increase in Ca2+ was absent in brain slices from GluRε2−/− mice that do not possess any functional NMDA receptors in the developing neocortex (Okada et al., 2003).
Uncertainties and Inconsistencies
The structural diversity of NMDA subunits can influence the functionality of the receptors and their permeability to Ca2+. For example, NR2B subunits show higher affinity for glutamate binding and higher Ca2+ permeability (reviewed in Higley and Sabatini, 2012). But NMDA receptor subunit composition is not the only parameter that influences Ca2+ entrance in the cytosol. Membrane potential due to pore blockade by extracellular Mg2+ and receptor phosphorylation are two additional regulator of Ca2+ influx through NMDA receptors (reviewed in Higley and Sabatini, 2012).
Entrance of Ca2+ into neuronal cell can also happen through KA and AMPA receptors but to a smaller extent compared to NMDA receptors (reviewed in Higley and Sabatini, 2012). However, recent findings suggest that AMPA receptors may also contribute to Ca2+ signalling during CNS development (reviewed in Cohen and Greenberg, 2008). Early in development cortical pyramidal neurons express calcium-permeable, GluR2 subunit–lacking AMPA receptors. During postnatal development these neurons undergo a switch in the subunit composition of AMPA receptors, expressing instead GluR2-containing, calcium-impermeable AMPA receptor suggesting that the main point entrance of Ca2+ at this developmental stage are NMDA receptors.
Furthermore, Ca2+ entry occurs through L- and H-type voltage-dependent Ca2+channels (L-VDCCs) (Perez-Reyes and Schneider, 1994; Berridge, 1998; Felix, 2005) that are encountered in neurons, suggesting that there are more possible entrance sites for Ca2+ to get into the cytosol rather than only through NMDA receptors.
Interestingly, Pb2+ has the ability to mimic or even compete with Ca2+ in the CNS (Flora et al., 2006). Indeed, Pb2+ is accumulated in the same mitochondrial compartment as Ca2+ and it has been linked to disruptions in intracellular calcium metabolism (Bressler and Goldstein, 1991). So, it can be that the reduced levels of Ca2+ after Pb2+ exposure may not be attributed to NMDA receptor inhibition but also to the ability of this heavy metal to compete with Ca2+. To make things more complicated, recent findings suggest that BDNF can also acutely elicit an increase in intracellular Ca2+ concentration, which is attributed not only to the influx of extracellular Ca2+ but also to Ca2+ mobilization from intracellular calcium stores (Numakawa et al., 2002; He et al., 2005). These findings derive from primary cultures of cortical neurons (E18 or 2-3 PND), where BDNF-evoked Ca2+ signals have not been altered neither by tetrodotoxin nor by a cocktail of glutamate receptor blockers (CNQX and APV), pointing out the importance of BDNF in Ca2+ homeostasis (Numakawa et al., 2002; He et al., 2005).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Besides the above studies described in rodents, intracellular Ca2+ regulation has been studied at the neuromuscular junction of larval Drosophila exposed to 0, 100 μM or 250 μM Pb2+ (He et al., 2009).
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Liu F, Patterson TA, Sadovova N, Zhang X, Liu S, Zou X, Hanig JP, Paule MG, Slikker W Jr, Wang C. (2013) Ketamine-induced neuronal damage and altered N-methyl-D-aspartate receptor function in rat primary forebrain culture. Toxicol Sci. 131: 548-557.
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Okada H, Miyakawa N, Mori H, Mishina M, Miyamoto Y, Hisatsune T. (2003) NMDA receptors in cortical development are essential for the generation of coordinated increases in [Ca2+](i) in "neuronal domains". Cereb Cortex. 13 :749-757.
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Sinner B, Friedrich O, Zink W, Martin E, Fink RH, et al. (2005) Ketamine stereoselectively inhibits spontaneous Ca2+-oscillations in cultured hippocampal neurons. Anesthesia and analgesia 100: 1660-1666.
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