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Modulation of NMDA receptors by glycine — introduction to some basic aspects and recent developments

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Summary

Glycine is a co-agonist at NMDA receptors and it's presence is a prerequisite for channel activation by glutamate or NMDA. Physiological concentrations reduce one form of NMDA receptor-desensitization. Interactions between the glycineB site and other domains of the NMDA receptor are complex and include the glutamate, Mg+ and polyamines sites. Glycine shows different affinities at various NMDA receptor subtypes probably via to allosteric interactions between NMDA2 subunits and the glycine recognition site on the NMDAR1 subunit. There is still some debate whether the glycineB site is saturatedin vivo but it seems likely that this depends on regional differences in receptor subtype expression, local glycine or D-serene concentrations and the expression of specific glycine transporters.

GlycineB antagonists and partial agonists have been reported to have good therapeutic indices as neuroprotective agents against focal ischaemia and trauma, anti-epileptics, anxiolytics, anti-psychotomimetics and in models of chronic pain. They clearly lack two potentially serious side effects classically associated with NMDA receptor blockade, namely neurodegenerative changes in the cingulate/retrosplenial cortex and psychotomimetic-like effects. This improved therapeutic profile may be partially due to the ability of full glycineB antagonists to reveal Gycne-sensitive desensitization and possibly also via functional and/or regional NMDA receptor subtype selectivity.

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  1. Department of Pharmacology, Merz + Co., Eckenheimer Landstrasse 100-104, D-60318, Frankfurt am Main, Germany

    C. G. Parsons, W. Danysz, M. Hesselink, S. Hartmann, B. Lorenz, C. Wollenburg & G. Quack

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Parsons, C.G., Danysz, W., Hesselink, M. et al. Modulation of NMDA receptors by glycine — introduction to some basic aspects and recent developments. Amino Acids 14, 207–216 (1998). https://doi.org/10.1007/BF01345264

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