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Binding of agonist, Ionotropic glutamate receptors leads to Overactivation, NMDARs
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment.||adjacent||High||Allie Always (send email)||Open for citation & comment||TFHA/WNT Endorsed|
Life Stage Applicability
Key Event Relationship Description
NMDARs can be activated indirectly through initial activation of KA/AMPARs as it happens in the case of DomA exposure. DomA is an agonist of presynaptic and postsynaptic KARs and sustained activation of these receptors by DomA results in massive ion flux and excessive release of glutamate from excitatory terminals causing depolarization of the postsynaptic neuron (as descibed in MIE). Upon this depolarization the Mg2+ block is removed from the pore of NMDARs, resulting in their activation allowing sodium, potassium, and, importantly, calcium ions to enter into a cell. The sustained exposure to DomA causes pathological overactivation of NMDARs. In the case of exposure to glufosinate NMDARs activation is triggered by direct, sustained binding of glufosinate to the NMDARs.
Evidence Supporting this KER
NMDARs are unique among ligand-gated ion channels in that their activation requires binding of two co-agonists, glycine and endogenous neurotransmitter, L-glutamate. Physiologically, however, glycine and glutamate have distinct functions. While L-glutamate is released from specific presynaptic terminals, low concentrations of ambient glycine present at the synapse are thought to be sufficient to allow receptor activation. There is a clear understanding that binding of glutamate or its analogue will activate NMDA receptor (accepted dogma). The prolonged activation of NMDARs will lead to a pathological over-activation of a receptor leading to excitotoxicity (minor role of KA/AMPARs), allowing high levels of calcium ions to enter the cell. However, KA/AMPARs play an important role for indirect NMDAR activation since (almost always) an initial activation of these receptors triggers depolarization of postsynaptic neurons that relieves the block of the channel pore by Mg2+, resulting in NMDAR activation. NMDA receptors are formed by a ligand binding domain (LBD) and an ion channel that are considered the core structural and functional elements of the receptors. There is a clear understanding of how agonist binding leads to channel opening that relies on structural (e.g. crystallography or NMR) and functional (e.g. UV and IR spectrometric measurements) experimental studies of the water-soluble LBD combined with functional studies of the intact receptor. After the initial agonist binding, a conformational change—so-called clam shell closure—that prevents agonist dissociation occurs followed by a conformational change in the ion channel that is tightly coupled to that in the LBD (reviewed in Traynelis et al., 2010). Consequently it can be stated that there is a clear structural and functional mechanistic understanding in this KER between MIE (Binding of agonist to glutamate ionotropic receptors) and KE1, NMDAR overactivation that, as explained above, can be triggered by direct binding to NMDAR or indirectly, through initial activation of KA/AMPARs as it happens in the case of exposure to glufosinate and DomA respectively, two stressors described in this AOP.
Indeed, domoic acid has a very strong affinity for the ionotropic glutamate receptors, the activation of which results in excitotoxicity, initiated by an integrative action of ionotropic receptors at both sides of the synapse blocking the channel from rapid desensitization. It has a synergistic effect with endogenous glutamate and it acts mainly as an agonist for presynaptic and postsynaptic kainate receptors. Activation of ionotropic receptors leads to the influx of Na+, K+ and Ca2+, particulary after activation of NMDARs. In combination with the inhibitory GABA neurotransmitter, glutamate contributes to the control of overall neuronal excitability.
Gufosinate (GLF) triggers alterations in glutamatergic signaling through direct binding and activation of NMDARs (Lantz et al., 2014: Matsumura et al., 2001). GLF agonist action at the NMDAR is expected to occur through interaction with the glutamate binding site and requires binding of the glycine co-agonist as well as release of the magnesium block from the channel pore. Additionally, the possible inhibition by GLF of the high affinity glutamate re-uptake transporter, especially GLT-I was studied to determine whether GLF could increase the levels of endogenous glutamate at the synaptic cleft, resulting in over activation of NMDARs. Such mechanism was excluded by Lantz (Lantz et al., 2014) but suggested by other studies (Watanabe and Sano, 1998).
Uncertainties and Inconsistencies
The increase in MFR induced by GLF in neuronal networks was significantly blocked by MK-801 but not entirely suggesting that GLF can increase activity in the MEA system through non-synaptic NMDARs, since these are not blocked by MK-801. It is not entirely clear whether GLF can work through an inhibition of the glutamate reuptake transporter, GLT-I, increasing the concentration of endogenous glutamate at the synaptic cleft and subsequently resulting in over activation of NMDARs (Lantz et al., 2014: Watanabe and Sano, 1998). Further studies are necessary to determine whether this alternative mechanism of GLF-induced NMDAR overactivation takes place. Additionally GLF also modulates glutamine synthetase (GS) activity. Since, astrocytic GS in the brain participates in the metabolic regulation of glutamate (endogenous agonist of NMDAR) it is not clear if this pathway contributes to NMDAR activation too.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Various studies suggest the existence of functional NMDA-like receptors in invertebrates (Xia et al., 2005). Fly and rodent NMDARs exhibit several important differences (Murphy and Glanzman, 1997). The expression and function of NMDA receptors in rodent and primates is well characterized in the existing literature.
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Blanke ML, VanDongen AMJ., Activation Mechanisms of the NMDA Receptor. In: Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press; 2009a. Chapter 13. Frontiers in Neuroscience.
Blanke ML., and Antonius M.J. VanDongen, Activation Mechanisms of the NMDA Receptor in Biology of the NMDA Receptor,2009b, Chapter 13, Van Dongen AM, editor. Boca Raton (FL): CRC Press.
Berman FW, Murray TF., Domoic acid neurotoxicity in cultured cerebellar granule neurons is mediated predominantly by NMDA receptors that are activated as a consequence of excitatory amino acid release. J Neurochem., 1997, 69: 693–703.
Enoki R, et al., NMDAR-mediated depolarizing after-potentials in the basal dendrites of CA1 pyramidal neurons. Neurosci Res., 2004, 48: 325-337.
Gibb AJ, Colquhoun D. Glutamate activation of a single NMDAR-channel produces a cluster of channel openings. Proc. R. Soc. Lond. (Biol.) 1991, 243: 39-47.
Giordano G, White CC, McConnachie LA, Fernandez C, Kavanagh TJ, Costa LG., Neurotoxicity of domoic Acid in cerebellar granule neurons in a genetic model of glutathione deficiency. Mol Pharmacol., 2006, 70: 2116–2126.
Jakobsen B, Tasker A, Zimmer J., Domoic acid neurotoxicity in hippocampal slice cultures. Amino Acids, 2002, 23: 37–44.
Lantz Stephen R , Cina M. Mack , Kathleen Wallace, Ellen F. Key , Timothy J. Shafer , John E. Casida, Glufosinate binds to N-methyl-D-aspartate receptors and increases neuronal network activity in vitro. NeuroToxicology, 2014, 45: 38–47.
Matsumura N1, Takeuchi C, Hishikawa K, Fujii T, Nakaki T., Glufosinate ammonium induces convulsion through N-methyl-D-aspartate receptors in mice. Neurosci Lett., 2001, 304(1-2): 123-5.
Murphy GG, Glanzman DL., Mediation of classical conditioning in Aplysia californica by long-term potentiation of sensorimotor synapses. Science, 1997, 278: 467-78.
Popescu G, et al. Reaction mechanism determines NMDAR response to repetitive stimulation. Nature. 2004, 430: 790-799.
Qiu S, Curras-Collazo MC., Histopathological and molecular changes produced by hippocampal microinjection of domoic acid. Neurotoxicol Teratol., 2006a, 28: 354–362.
Qiu S, Pak CW, Curras-Collazo MC., Sequential involvement of distinct glutamate receptors in domoic acid-induced neurotoxicity in rat mixed cortical cultures: Effect of multiple dose/duration paradigms, chronological age, and repeated exposure. Toxicol Sci., 2006b, 89: 243–256.
Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R., Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev., 2010, 62(3):405-96.
Vale-Gonzalez C, Alfonso A, Sun˜ol C, Vieytes MR, Botana LM., Role of the plasma membrane calcium adenosine triphosphatase on domoate-induced intracellular acidification in primary cultures of cerebellar granule cells. J Neurosci Res., 2006, 84: 326–337.
Watanabe T1, Sano T., Neurological effects of glufosinate poisoning with a brief review. Hum Exp Toxicol. 1998, 17: 35-9.
Xia S, et al., NMDARs mediate olfactory learning and memory in Drosophila. Curr Biol., 2005, 15:603-618.