Ionotropic Glutamate Receptor Classification. There are three major types of ionotropic glutamate receptors (iGluRs), which are named after the agonists that were originally identified to activate them selectively, and are therefore called N-methyl-D-aspartate (NMDA), α-amino- 3-hydroxy-5-methyl-4- isoazolepropionic acid (AMPA) and 2-carboxy-3-carboxymethyl-4-isopropenyl- pyrrolidine (kainate) receptors. The receptors appear to be tetrameric (Xxxxx et al., 1998) or pentameric and the subunits that comprise these are specific for each of the three families (Xxxxxxxxxx and Conn, 2000). The subunit composition determines the biophysical properties of the receptor and to a variable extent its pharmacology. Even though iGluRs share common structural features, the overall amino acid identity across the three families is only in the 20–30% range (Kew and Xxxx, 2005). Ionotropic glutamate receptor subunits possess an extracellular amino terminal domain, which exhibits homology to the metabotropic glutamate receptor (mGluR) bi-lobed agonist binding domain, followed by a first transmembrane domain and then a pore forming membrane-residing domain that does not cross the membrane but forms a reentrant loop entering from and exiting to the cytoplasm. The second and third transmembrane domains are linked by a large extracelluar loop and the third transmembrane domain is followed by an intracellular carboxy terminus (Xxxxxxxxxx et al., 1999; Kew and Xxxx, 2005; Xxxxx and Xxxxxxxxx, 2004). The NMDA receptor family is composed of seven subunits, NR1, NR2A–D and NR3A and B, which are all products of separate genes. The NMDA receptor is unique amongst ligand-gated ion channels in its requirement for two obligatory co-agonists, binding at the glycine and glutamate binding sites localized on the NR1 (Xxxxxxxx et al., 1994); (Hirai et al., 1996; Kew et al., 2000; Xxxxxxx et al., 1995) and NR2 (Anson et al., 1998; Xxxxx et al., 1997) subunits, respectively. NMDA receptors are of tetrameric structure and are likely composed of pairs of dimers (Kew and Xxxx, 2005) AMPA receptors are composed of a four-subunit family (GluR1–4) that are products of separate genes and are thought to assemble as either pentamers or tetramers (Rosenmund et al., 1998). Like NMDA receptors, native AMPA receptors are likely heteromeric in composition. The GluR2 subunit plays a critical role in determination of the permeability of heteromeric receptors to Ca2+. Thus, AMPA receptors that do not contain GluR2 are permeable to Ca+2 and show marked inward...
