Subunit Dependent Modulation of Ionotropic Glutamate Receptors

The classical competitive blockers of the glutamate site on NMDA receptors are phosphono derivatives of short-chain (five to seven carbons) amino acids such as 2-amino-5-phosphonopentanoic acid. In contrast, the glycine site of NMDA receptors, as well as the glutamate sites of AMPA and kainate receptors, are competitively blocked by halogenated quinoxalinediones and kynurenic acid derivatives. However, numerous compounds have been identified that act on modulatory sites of NMDA receptors and, to a lesser extent, AMPA and kainate receptors. We will concisely review the pharmacology of these modulatory sites, particularly as they relate to cognitive or addictive processes.

4.3.1. Noncompetitive Antagonists of NMDA Receptors

Several addictive or abused drugs inhibit NMDA receptors, often in a subunit-dependent fashion. Ethanol noncompetitively inhibits recombinant or native NMDA receptors at intoxicating concentrations, inhibition being more pronounced at NR2A- or NR2B-containing receptors than those with NR2C or NR2D (102). Inhibition of NR1/NR2A (but not NR2B) receptors was reduced by expression of a-actinin protein (103), which links the NR1 and NR2B subunits to actin and thus to the cytoskele-ton (104). Interestingly, treatment of ethanol-dependent mice with a selective NR2B-containing NMDA receptor antagonist, ifenprodil, reduced the intensity of ethanol withdrawal signs (105). Moreover, chronic exposure of mice to ethanol increased expression of NR2B subunit protein in the limbic forebrain; the two findings together are suggestive of a role for NR2B upregulation in the development of physical dependence to ethanol (105). At higher concentrations, ethanol also inhibits native AMPA receptors expressed by neurons of the medial septum/diagonal band (106).

Nitrous oxide (laughing gas) at anesthetic concentrations and toluene, two inhaled drugs of abuse, are noncompetitive NMDA receptor blockers (107,108). The effect of toluene is strongest at NR2B-containing receptors, but little is known about the nitrous oxide effect.

Protons inhibit NMDA receptors that lack exon 5 of the NR1 subunit, with half-inhibition near pH 7.4; exon 5 is a very basic short extracellular loop that is thought to act as a tethered modulator of NMDA receptor gating (109). Ifenprodil is the exemplar of an important class of NR2B-selective NMDA receptor antagonists. These drugs inhibit receptor activation by potentiating proton inhibition of the receptors (110). Inhibition by ifenprodil is occluded if the NR1 subunit contains exon 5. Zinc appears to play a similar role for NR2A-containing NMDA receptors (111,112). Paoletti et al. (113) have proposed a structure near the N-terminus of NR2A that binds zinc in a clamshell-like cleft (Fig. 6); presumably, a similar structure in NR2B binds ifenprodil and related compounds.

4.3.2. Modulators of Desensitization of AMPA and Kainate Receptors

A prominent molecular determinant of AMPA receptor desensitization is the flip/flop alternative exon, which is a helical region lying on a solvent-exposed surface of the subunit in the third extracellular loop (Fig. 3A-C). Receptors with subunits containing predominantly the flop exon have threefold to fivefold faster desensitization than those with the flip variants (114). Several drug classes, as typified by cyclothiazide and the cognitive enhancer aniracetam, have been identified that modulate desensiti-zation of AMPA receptors. The effects of cyclothiazide on AMPA receptors are strongly influenced by the Ser/Asn residue at position 750. Conversion of Ser750 in GluR1flip to glutamine, which is the

Fig. 6. Structure of the NR2A subunit as proposed by Paoletti et al. (113). extracellular domains form two clamshell-like binding domains, both homologous to bacterial periplasmic amino-acid-binding proteins (LIVBP and LAOPB). The very N-terminal LIVBP-like domain acts as a Zn2+ sensor and the LAOPB-like domain binds the agonist glutamate. (From ref. 113, with permission of Elsevier Science and P. Paoletti.)

Fig. 6. Structure of the NR2A subunit as proposed by Paoletti et al. (113). extracellular domains form two clamshell-like binding domains, both homologous to bacterial periplasmic amino-acid-binding proteins (LIVBP and LAOPB). The very N-terminal LIVBP-like domain acts as a Zn2+ sensor and the LAOPB-like domain binds the agonist glutamate. (From ref. 113, with permission of Elsevier Science and P. Paoletti.)

homologous residue found in the cyclothiazide-insensitive kainate receptors, abolishes cyclothiazide actions on AMPA receptors (115). Conversely, the introduction of a serine residue into the homologous site on GluR6 imparts cyclothiazide sensitivity (115).

Kainate receptor desensitization is insensitive to cyclothiazide, but it can be irreversibly reduced by concanavalin A, a lectin carbohydrate (116). Concanavalin A is effective only for receptors containing GluR5 or GluR6, but not GluR7, suggesting different glycosylation patterns between GluR7 and GluR5/6 (117).

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