AMPA-receptors

Selective agonists of KAR include SYM 2081, (2S,4R)-4-methylglutamic acid 5-1-Will, 5-iodowillardiine and 2S,4R isomers of 4-cinnamyl and 4-allylglutamate (Fig. 2.4) (Chittajallu et al., 1999 Pedregal et al., 2000). AMOA, (RS)-2-amino- 

3- [3-(carboxymethoxy)-5-methylisoxazol-4-yl]propionic acid AMNH, (RS)-2-amino-3-[2-(3-hydroxy-5-methylisoxazol-4-yl)-methyl-5-methyl-3-oxoisoxazolin- 

3 Glutamate Receptors and Glutamate-Mediated Neural Cell Death 

The mechanisms underlying glutamate and its analog-induced neuronal damage are quite complex. The molecular sequence of these events is not fully understood. The mechanisms include inhibition of mitochondrial function and increases 

Bates B., Xie Y., Taylor N., Johnson J., Wu L., Kwak S., Blatcher M., Gulukota K., and Paulsen J. E. (2002). Characterization of mGluR5R, a novel, metabotropic glutamate receptor 5-related gene. Brain Res. Mol. Brain Res. 109 18-33. 

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Both AMPA and NMDA receptors are multimeric, probably tetrameric, assemblies of various molecularly distinct subunits, giving rise to large receptor diversity. For AMPA receptors this is achieved by assembling the... 

Interestingly, the genomic sequences of all AMPA receptor subunits contain a Q codon for this position and the R codon is selectively introduced into the GluR-B pre-mRNA by RNA editing [3]. Additionally, the Q/R site is a critical determinant of current... 

In contrast to AMPA receptors, NMDA receptor channels display a prominent Ca2+ permeability, which is largely independent ofthe subunit composition. It has been shown by mutational analysis that the Ca2+ permeability of recombinant NMDA receptors is dependent on a residue at a position equivalent to the Q/R site of AMPA subunits. Both NR1 and NR2 subunits contain an asparagine (N) residue at this position. Replacing this N with an R within the NR1 subunit led to the formation of NMDA receptors with a strongly reduced Ca2+ permeability, whereas exchanging N for Q in the NR2 subunit had only a small effect,... 

Antagonists selective for kainate receptors are not available yet. The non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) blocks AMPA as well as kainate receptors. Nevertheless, compounds like GYKI53655, which acts as a noncompetitive antagonist of AMPA receptors and completely blocks AMPA receptor function at certain concentrations at which no antagonistic effect on kainate receptors is discernible, has been used to demonstrate the kainate receptor-mediated currents in neurons. 

The AMPA receptors for glutamate, the nicotinic acetylcholine receptor and the 5-HT3-receptor for serotonin are cation channels (Table 1). When they open, the major consequence is a sudden entry of Na+, depolarization and an excitatory postsynaptic potential (EPSP Fig. 1). 

Van Sickle BJ, Tietz El Selective enhancement of AMPA receptor-mediated function in hippocampal CAl nemons from chronic benzodiazepine-treated rats. Nemo-pharmacology 43 11—27, 2002... 

Some derivatives of adamantane with antagonist or agonist effects have also been synthesized. For instance, monocationic and dicationic adamantane derivatives block the a-amino-3-hydroxy-5-methylisoxazole -propionic acid (AMPA) receptors, A-methyl-o-aspartate (NMDA) receptors [134—136] and 5-hydroxytryptamine (5-HT3) receptors [137]. 

Meden P, Overgaard K, Sereghy T, Boysen G. Enhancing the efficacy of thrombolysis by ampa receptor blockade with nbqx in a rat embolic stroke model. J Neurol Sci 1993 119 209-216. 

AMPA receptors can be formed by homomeric or heteromeric combinations of GluRl-4. However, most native AMPA receptors are more likely to be heteromeric assemblies... 

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