Glutamate receptors excitotoxicity

The forces driving water flow to form cytotoxic edema are osmotic, generated in brain injury conditions (ischemia, trauma, hypoxia) by disturbances in ionic homeostasis due to failure of the Na /K+ ATPase and/or dramatic influx of Na" and Ca " via ionotropic glutamate receptors (excitotoxicity) and other ionic channels. These pathological alterations in cellular ionic homeostasis result in Na" " and water flow from the intravascular and extracellular space into the intracellular compartment. 

A wide variety of acute and chronic neurological diseases may be mediated, at least in part, by a final common pathway of neuronal injury involving excessive stimulation of glutamate receptors. Excitotoxicity is known to have an important effect on neurone degeneration in certain acute disease states such as ischaemia, trauma and epilepsy. For neurodegenerative diseases, it is assumed that the same type of effect would occur. There are several arguments in favour of this hypothesis. 

Excitotoxicity Direct and Indirect Activation of Glutamate Receptors... 

In vitro studies on excitotoxicity suggest that while both NMDA and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainate (KA) receptors can mediate excitotoxicity (see Ch. 15), these classes of glutamate receptors do not do so equally. Experiments with cortical or hippocampal cell cultures suggest that much of the neuronal death associated with brief, intense glutamate exposure is mediated by NMDA receptor activation, probably because this can induce lethal amounts of Ca2+ influx more rapidly than can AMPA/KA receptor stimulation. 

However, overactivation of AMPA or KA receptors can also lead to intracellular Ca2+ overload and neurodegeneration. This maybe especially true under conditions where NMDA-receptor activity is reduced by extracellular acidity or a buildup of extracellular Zn2+ [ 12]. It is also true with respect to specific neuronal subpopulations that express AMPA-sensitive Ca2+ channels (see Ch. 15). G-protein-linked metabotropic glutamate receptors (mGluRs) appear not to mediate excitotoxicity directly but, rather, to modify the degree of excitotoxic injury. 

Deng WB, Wang H, Rosenberg PA, et al (2004) Role of metabotropic glutamate receptors in oligodendrocyte excitotoxicity and oxidative stress. Proc Natl Acad Sci USA 101 7751-7756... 

The NMDA, AMPA, and kainate subtypes of glutamate receptors are probably all linked to an ion channel. The metabotropic glutamate receptor subtype, however, belongs to the G protein—linked superfamily of receptors. The specific functioning of the various subtypes of glutamate receptors is the focus of intense debate. The actions at NMDA receptors will be emphasized here in our discussions on excitotoxicity. 

Michaelis E. K. (1998). Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog. Neurobiol. 54 369—415. 

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