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Key Event Title
Binding of agonist, NMDARs
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
Key Event Description
How It Is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
1. Ex vivo: The most common assay used is the NMDA receptor (MK801 site) radioligand competition binding assays (Reynolds, 2001; Gao et al., 2013; http://pdsp.med.unc.edu/UNC-CH%20Protocol%20Book.pdf; http://www.currentprotocols.com/WileyCDA/CPUnit/refId-ph0120.html). This assay is based on the use of the most potent and specific antagonist of this receptor, MK801 that is used to detect and differentiate agonists and antagonists that bind to this specific site of the receptor.
2. In silico: The prediction of NMDA receptor targeting is achievable by combining database mining, molecular docking, structure-based pharmacophore searching, and chemical similarity searching methods together (Koutsoukos et al., 2011; Gao et al., 2013).
Domain of Applicability
The major determinants for ligand e.g. for both co-agonist glycine binding and L-glutamate binding are well-conserved between species from lower organism to mammals (reviewed in Xia and Chiang, 2009). PCR analysis, cloning and subsequent sequencing of the seal lion NMDA receptors showed 80% homology to those from rats, but more than 95% homology to those from dogs (Gill et al., 2010).
Pulido OM. Domoic acid toxicologic pathology: a review. Mar Drugs. 2008. 6: 180-219.
Gill S, Goldstein T, Situ D, Zabka TS, Gulland FM, Mueller RW. Cloning and characterization of glutamate receptors in Californian sea lions (Zalophus californianus). Mar Drugs. 2010. 8: 1637-1649.
Traynelis S, 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: 405-496.
Xia S, Chiang AS. NMDA Receptors in Drosophila. In: Van Dongen AM, editor. Biology of the NMDA Receptor. Boca Raton (FL): CRC Press; 2009. Chapter 10. Available from: http://www.ncbi.nlm.nih.gov/books/NBK5286/
F. W. Berman and T. F. Murray, “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,” Journal of Neurochemistry, vol. 69, no. 2, pp. 693–703, 1997. View at Google Scholar · View at Scopus
F. W. Berman, K. T. LePage, and T. F. Murray, “Domoic acid neurotoxicity in cultured cerebellar granule neurons is controlled preferentially by the NMDA receptor Ca2+ influx pathway,” Brain Research, vol. 924, no. 1, pp. 20–29, 2002. View at Publisher · View at Google Scholar · View at Scopus
Watanabe KH, Andersen ME, Basu N, Carvan MJ 3rd, Crofton KM, King KA, Suñol C, Tiffany-Castiglioni E, Schultz IR. (2011). Defining and modeling known adverse outcome pathways: Domoic acid and neuronal signaling as a case study. Environ Toxicol Chem 30:9-21.