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Vol. 299, Issue 1, 12-20, October 2001
Neuroscience Research Division, Lilly Research Laboratories, Eli
Lilly and Company, Indianapolis, Indiana
Metabotropic glutamate (mGlu) receptors, which include mGlu1-8
receptors, are a heterogeneous family of G-protein-coupled 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.
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