33,34 Three different subgroups of glutamatergic ion channels have been identified utilizing their pharmacological ability to bind different synthetic ligands, each of which is composed of a different set of subunits. These are the NMDA receptor (NMDAR), the AMPA receptor (AMPAR), and the kainate receptor (KAR).The latter two groups are often referred to together as the “non-NMDA” receptors, but undoubtedly subserve unique functions (Table I). In the adult mammalian brain, Inhibitors,research,lifescience,medical NMDA and AMPA glutamatergic INCB024360 purchase receptors are colocalized in approximately 70% of the synapses.36 By contrast, at early stages of development, synapses are more likely to contain only

NMDA receptors. Radioligand binding studies have shown that NMDA and AMPA receptors are found in high density in the cerebral cortex, hippocampus, striatum, septum, and amygdala. Table I. Receptor subtype units. Once released from the presynaptic terminal, glutamate is able to bind to numerous excitatory amino acid (EAA) receptors, Inhibitors,research,lifescience,medical including

both ionotropic (eg, N-methyl-D-aspartate [NMDA]) and metabotropic receptors. Presynaptic regulation … NMDA receptors The NMDA receptor is activated by glutamate and requires Inhibitors,research,lifescience,medical the presence of a coagonist, namely glycine or D-serine, to be activated. However, the binding of both glutamate and glycine is still not sufficient for the NMDA receptor channel to open, since, at resting membrane potential, the NMDA ion channel is blocked by Mg2+ ions. Only when the membrane is depolarized (eg, by the activation of AMPA or kainate receptors Inhibitors,research,lifescience,medical on the same postsynaptic neuron) is the Mg2+ blockade relieved. Under these conditions, the NMDA receptor

channel will open and permit the entry of both Na+ and Ca2+ (Figure 1). The NMDA receptor channel is composed of combination Inhibitors,research,lifescience,medical of NR1, NR2A, NR2B, NR2C, NR2D, NR3A, and NR3B subunits (Table I). The binding site for glutamate has been localized to the NR2 subunit and the site for the coagonist glycine has been localized to the NRl subunit, which is required for receptor function. Two molecules of glutamate and two of glycine arc thought to be necessary to activate the ion channel. Within the Adenylyl cyclase ion channel, two other sites have been identified called the sigma (a) site and the phencyclidine (PCP) site. The hallucinogenic drug PCP, ketaminc, and the experimental drug dizocilpine (MK-801), all bind at the latter site and are considered noncompetitive receptor antagonists that inhibit NMDA receptor channel function. In preclinical studies, drugs of this type have been shown to have neuroprotective properties against anoxia and hypoglycemia; these studies await clinical confirmation.