NMDA receptors recognition sites

PCP is not acting as a competitive inhibitor at the NMDA receptor thus, PCP and NMDA probably do not share a common recognition site. Examination of the effect of PCP on NMDA-induced DA release (figure 1, lower panel) tends to support this conclusion, but is compromised somewhat by the slightly nonparallel shift produced by 2-APV. This may be due to the fact that NMDA may partially activate quisqualate and kainate receptors on those neurons that are not antagonized by 2-APV. 

Zorumski, C. F., Yamada, K. A., Price, M. T and Olney, J. W. (1993) A benzodiazepine recognition site associated with the non-NMDA glutamate receptor. Neuron 10,61-67. 

While its mechanism of action has not been clearly established, felbamate shows some activity as an inhibitor of voltage-dependent sodium channels in a manner similar to that of phenytoin and carbamazepine. Felbamate also interacts at the strychnine-insensitive glycine recognition site on the NMDA receptor-ionophore complex. Whether this effect is important to its anticonvulsant activity is not clear. 

The discovery of potent and selective agonists and antagonists (Figs. 2.1, 2.2, and 2.3) has resulted in extensive information on the NMDA receptor-channel complex (Wood et al., 1990 Fagg and Baud, 1988). It consists of four domains (1) the transmitter recognition site with which NMDA and L-glutamate interact ... 

The NMDA receptor ion-channel complex has been demonstrated to play an important role in spinal nociceptive transmission (Dickenson et al., 1997 Zhang et al., 2002). In addition to possessing the NMDA receptor, to which glutamate binds, the NMDA receptor ion-channel complex contains several allosteric sites such as polyamine and glycine recognition sites that modulate the receptor function (for a review, see Williams et al., 1991). Our behavioral studies indicate that both spinal polyamine and glycine recognition sites of the NMDA receptor ion-channel complex play the crucial role in nociceptive transmission (Tan-No et al., 2000, 2007). 

In summary, evidence is presented that i.t.-administered big dynorphin at extremely low doses produces nociceptive behavior. This effect seems to be mediated through the activation of the NMDA receptor ion-channel complex by acting on the polyamine recognition site because the peptide has a strong positive charge. 

Fig. 2. The possible mechanism of NEM-induced nociceptive behavior. NEM inhibits the degradation of endogenous dynorphins, presumably big ( Kuorphin. and accumulated dynorphins activate the NMDA receptor ion-channel complex by acting on the polyamine recognition site and then induce nociceptive behavior. Dyn dynorphin.

NMDA receptors ( Figure 1.3-2) are the most complex of the ionotropic receptors. In addition to the recognition site for glutamate, NMDA receptors contain several allosteric modulatory sites, including (1) a site for the endogenous brain amino acids glycine and D-serine, (2) a polyamine-sensitive site, and (3) a redox site that is sensitive to glutathione (see Chapter 2.5 this volume). All sites act primarily to facilitate activity at the receptor. 

Williams, K., Dawson, V.L., Romano, C., Dichter, M.A. and Molinoff, P.B. (1990). Characterization of polyamines having agonist, antagonist, and inverse agonist effects at the polyamine recognition site of the NMDA receptor. Neuron 5 199-208. 

A benzodiazepine recognition site associated with the non-NMDA glutamate receptor. Neuron 10 61-67. 

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