NMDA receptors structure

Leeson PD, Iversen LL (1994) The glycine site on the NMDA receptor structure-activity relationships and therapeutic potential. J Med Chem 37(24) 4053-4067... 

Kuryatov, A., Laube, B., Betz, H., Kuhse, J. Mutational analysis of the glycine binding site of the NMDA receptor Structural similiarity with bacterial amino acid binding proteins, Neuron 1994, 12, 1291-1300. 

Schrattenholz A. and Soskic V. (2006). NMDA receptors are not alone dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol-rich membrane domains leads to disease-specific nuances of glutamate signalling. Curr. Top. Medicinal Chem. 6 663-686. 

These include nicotinic acetylcholine receptors, neuronal calcium channels, muscle sodium channels, vasopressin receptors, and iV-methyl-D-aspartate (NMDA) receptors. Some general features of the structure, function, and evolution of biologically active peptides isolated from Conus venom are presented. 

The NMDA receptor has a heteromeric structure composed of two subunit types NRl and NR2, the latter having four subunits (NR2A-NR2D) (Fig. 10.2). Molecular genetic techniques have demonstrated that native NMDA receptors are likely to be composed of a combination of the NRl subunit (which can exist in eight different splice variants) and one or more of the four NR2 subunits which are the main determinants of functional diversity among the NMDA receptors (see Chapter 3 for further details). It has been shown that there are distinct developmental and spatial expression patterns of NMDA receptor NRl subunit splice variants and NR2 receptor subunits in the CNS. 

Figure 10.4 Structures of some antagonists at the various receptors for glutamate. CNQX is an AMPA antagonist but NQQX has greater selectivity. AP-5 is an NMDA receptor antagonist while MK-801 blocks the NMDA receptor channel (non-competitive)...

Our first studies with compounds that alter Glu neurotransmission were not targeted at decreasing brain excitability. Rather, as noted above, we used the limbic hypermetabolism induced by non-competitive NMDA receptor antagonists to test whether an increase in the metabolic rate of these limbic structures... 

Kuner, T., Wollmuth, L. P., Karlin, A., Seeburg, P. H. and Sakmann, B. Structure of the NMDA receptor channel M2 segment inferred from the accessibility of substituted cysteines. Neuron 17 343-352,1996. 

While the conditional gene knockout experiments are supportive of a role for the NMDA receptors in memory, they are less than fully conclusive in linking the synaptic coincidence-detection feature of the NMDA receptor to memory formation. Like all loss-of-function studies, CA1-specific gene-knockout experiments could, in theory, produce memory impairment via a mechanism independent of the coincidence-detection function of the NMDA receptor. For example, one may argue that the physical absence of the NMDA receptor channels may cause subtle structural reconfiguration at the synapse, thereby altering normal synaptic transmission. Therefore, the memory impairment in CA1-specific NR1 knockout mice does not allow a firm conclusion that the coincidence-detection function of NMDA receptors controls learning and memory processes at the cellular level. 

Excitatory amino acids Ibotenic acid is structurally related to glutamate, the principal excitatory neurotransmitter, and it activates NMDA receptors (Madsen et al. 1990 Mayer and Westbrook 1987 Schwarcz et al. 1979 Honore et al. 1981). 

There is one additional drug approved for use in moderate to severe cases of AD memantine, marketed as Namenda. Memantine works by a distinct mechanism it has moderate affinity for A-methyl-D-aspartate (NMDA) receptors and is the only approved molecule for moderate to severe AD in this structural class. We should be grateful for the AD drugs that we do have but the fact is that there is an enormous need for far better ones. 

The ionotropic receptors have a pentameric structure. The most important of these, the NMDA receptors, are assembled from two... 

In contrast to the ionotropic receptors, the metabotropic receptors are monomeric in structure and unique in that they show no structural similarity to the other G-protein-coupled neurotransmitter receptors. They are located both pre- and postsynaptically and there is experimental evidence that they are involved in synpatic modulation and excitotoxicity, functions which are also shared with the NMDA receptors. To date, no drugs have been developed for therapeutic use which are based on the modulation of these receptors. 

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