Perspectives in Pharmacology Unveiling the Functions of Presynaptic Metabotropic Glutamate Receptors in the Central Nervous System

Metabotropic glutamate (mGlu) receptors, which include mGlu1–8 receptors, are a heterogeneous family of G-proteincoupled receptors which function to modulate brain excitability via presynaptic, postsynaptic and glial mechanisms. Certain members of this receptor family have been shown to function as presynaptic regulatory mechanisms to control release of neurotransmitters. In general, Gi-coupled mGlu receptor subtypes appear to negatively modulate excitatory (and possibly also inhibitory) neurotransmitter output when activated. Localization studies have shown that mGlu7 is restricted to the presynaptic grid at the site of vesicle fusion. These studies along with other evidence suggest that mGlu7 is the nerve terminal autoreceptor that regulates physiological release of glutamate. Other mGlu subtypes, in particular mGlu2, mGlu8, and possibly mGlu4, are also localized presynaptically, but at perisynaptic sites outside the active zone of neurotransmitter release. Gi-coupled mGlu receptors also may exist on presynaptic elements of neighboring -aminobutyric acid (GABA) neurons where they play a role in heterosynaptic suppressions of GABA release. This suggests that these receptors may have evolved to monitor glutamate that has “spilled” out of the synapse. Thus, they may serve as the brain’s evolutionary mechanism to prevent pathological changes in neuronal excitability and thus maintain homeostasis. Recent progress on the molecular and pharmacological aspects of these presynaptic mGlu receptors is unveiling their functions and the therapeutic directions of agents designed for these novel glutamate receptor targets. In the past decade there has been considerable progress in the field of metabotropic or G-protein-coupled glutamate (mGlu) receptors. For the most part, the cloning and identification of a novel heterogeneous family of mGlu receptors has driven this progress. There are currently eight known subtypes of mGlu receptors, which have been classified into three groups (see Table 1). Members of the mGlu receptor family are each G-protein-coupled receptors (GPCRs). Within each mGlu receptor group, there is 70% sequence homology, whereas between the mGlu receptors subgroups there is lesser ( 40%) homology. Group I mGlu receptors include mGlu1 and mGlu5, which when expressed are coupled via Gq to phospholipase C. Group II (mGlu2 and mGlu3) and group III (mGlu4,6,7,8) receptors are coupled to Gi and inhibit stimulated cAMP formation when expressed in cell lines. A number of gene splice variants for group I and III mGlu receptors are also known, with most amino acid changes in the carboxylterminal regions that may be important in targeting receptors to regions of the cell (Boudin et al., 2000). These receptors each have unique but overlapping distributions in the central nervous system, and the functions of each subtype within these groups have recently been an active area of neuroscience research. In general, mGlu receptors appear to have evolved as modulatory mechanisms to control CNS excitability. Many disorders of the central nervous system, including psychiatric as well as neurological, have been linked to alterations in neuronal excitability via the glutamatergic system (Danysz et al., 1995). Thus, understanding ways to modulate CNS excitability by glutamate receptor mechanisms has broad therapeutic significance. In particular, certain members of the group II and group III mGlu receptors have been implicated in presynaptic negative modulation of excitatory glutamate and/or ABBREVIATIONS: mGlu, metabotropic glutamate; GPCRs, G-protein-coupled receptors; CNS, central nervous system; GABA, -aminobutyric acid; EPSP, excitatory postsynaptic potential; MCPG, -methyl-carboxyphenylglycine; 5HT, serotonin; L-AP4, L-2-amino-4-phosphonobutyric acid; 3,4-DCPG, (S)3,4-dicarboxyphenyl glycine; AMPA, -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-D-aspartate; nRT, thalamic reticular nucleus. 0022-3565/01/2991-12–20$3.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 299, No. 1 Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics 900048/927055 JPET 299:12–20, 2001 Printed in U.S.A. 12 at A PE T Jornals on A uust 0, 2017 jpet.asjournals.org D ow nladed from