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Note: For further information, see, for example, 9. The full names of the abbreviated compounds in alphabetical order are as follows: L-AP4, L-(+)-amino-4-phosphonobutyric acid; APCD, 4-aminopyrrolidine-2,4-dicarboxylic acid; CBPG, (S)-(+)-2-(3'-dicarboxycyclopropyl(1.1.1)pentyl)-glycine; CHPG, (K,S)-2-chloro-5- hydroxyphenylglycine; CPCCOEt, cyclopropan[^]chromen-1a-carboxylate; DCG-VI, (2'S,2'^,3'K)-2-(2'3'-dicarboxycyclopropyl)glycine; DHPG, 3,5-dihydroxyphenylglycine; LY341495, 2S-2 amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-xanth-9-yl)propanoic acid; LY354740,(1S,2S,5K,6S)-(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; LY367385, (+)-2-methyl-4-carboxy-phenylglycine; MAP4, a-methyl-l-amino-4-phosphonobutyrate; PPG, (K,Sj-4-phosphonophenylglycine; L-SOP, l-serine O-phosphate.

a Note that at high concentrations, the group II mGluR antagonist LY341495 can also block group III and I receptors.

Fig. 1. Example of physiological roles of mGluRs at the Schaffer collateral synapse in CA1 in the hippocampus. mGluR5 and mGluR7 are located in the presynaptic terminal, where they inhibit glutamate release directly by effects on the release machinery or indirectly by inhibiton of voltage-gated calcium channels. mGluR5 is expressed at the postsynaptic terminal which increases pyramidal cell excitability by reducing potassium currents. Moreover, mGluR5 activation can potentiate NMDA receptor-mediated currents. Inhibitory GABA-ergic terminals express group I mGluRs, and by inhibiting GABA release, they can indirectly increase pyramidal cell excitability. Finally, glial cells express mGluR3. There is evidence that glial mGluR stimulation leads to release of a neuroprotective factor. Also, mGluR3 activation can potentiate P-adrenergic responses, leading to release of cAMP or adenosine, which stimulates A1 adenosine receptors and reduces glutamate release from the presynaptic terminal. (From ref. 13, with permission.) (Color illustration in insert following p. 142.)

A mGluRI 7TMs i Ia mGluRS

mGluRS

b mGluR4

mGluR7

mGluR8

Fig. 2. Schematic representation of splice variants of mGluR proteins. Only translated regions are depicted; alternative splicing in untranslated regions is not shown. The seven transmembrane domains are shown in black. The different C-terminal domains are indicated by different patterns. (A) Group I mGluRs. The mGluRla C-tail is homologous to those of mGluR5a and mGluR5b (all shown in gray). The C-terminal domains of mGluR5a and mGluR5b are the same. (B) Within the group III mGluRs, no homology between C-terminal domains is found. Adapted from ref. 7; new splice variants for mGluR7 and mGluR8 (14,15) are added.

Some mGluRs are alternatively spliced. Alternative splicing in translated regions occurs only at the C-termini in mGluRI, 4, 5, 7, and 8, as shown Fig. 2. In some cases, alternative splicing leads to different interactions with other signaling molecules (see Section 2.2.).

2.2. Association with Other Intracellular Signaling Proteins and Targeting Proteins

In addition to mGluR signaling via G-protein cascades, mGluR interactions with other signaling molecules are being discovered. For example, group I mGluRs with homologous C-termini (mGluRla and mGluR5) couple to Homer proteins (16). Constitutively expressed Homer proteins (the long forms of Homer lb, lc, 2, and 3) physically link mGluRla or mGluR5 to the endoplasmic IP3 receptor. This signaling complex can be disrupted by the truncated Homer la, which is up-regulated as an immediate early gene after certain forms of long-term potentiation and after seizures. Similarly, the long Homer forms inhibited group I mGluR-mediated regulation of N-type calcium channels and M-type potassium channels, whereas the truncated forms did not (17). Moreover, Homer interacts with the scaffold protein Shank, which links Homer to many other cytoplasmic and membrane proteins. By virtue of its ability to bridge receptors and cytoplasmic proteins, Homer controls the trafficking of mGluRla and mGluR5 into and out of synapses (18).

In addition to linking mGluRs to signaling molecules, the mGluR C-termini can be involved in receptor targeting, as observed in other receptors. For example, the last 60 amino acids target mGluR7 to axons and dendrites, whereas mGluR2 is excluded from axons (19). Calmodulin binds to C-terminal regions of mGluR5 and mGluR7, which are also phosphorylated by protein kinase C (PKC) (20-22). Calcium/calmodulin binding and PKC phosphorylation are mutually occlusive, similar to their roles at NMDA receptors (see Section 3.7.). Moreover, mGluR7 seems to be able to associate with the PKC a-subunit and protein interacting with C-kinase l (PICKl), because they can be coim-munoprecipitated from transfected COS cells and PICKl can reduce phosphorylation of mGluR7a in

Table 2

Glutamate Receptor Subunits and Their Genes

Table 2

Glutamate Receptor Subunits and Their Genes

Group

Receptor Family

Subunit

Gene

Chromosome (human)

GenEmbl accession numbers Mouse Rat Human

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