It is thought that mGluRs play a role in a variety of different functions.
Modulation of other receptors Metabotropic glutamate receptors are known to act as modulators of (affect the activity of) other receptors. For example, group I mGluRs are known to increase the activity of
N-methyl-D-aspartate receptors (NMDARs), a type of ion channel-linked receptor that is central in a
neurotoxic process called
excitotoxicity. Proteins called
PDZ proteins frequently anchor mGluRs near enough to NMDARs to modulate their activity. It has been suggested that mGluRs may act as regulators of neurons' vulnerability to excitotoxicity (a deadly neurochemical process involving glutamate receptor overactivation) through their modulation of NMDARs, the receptor most involved in that process. Excessive amounts of
N-methyl-D-aspartate (NMDA), the selective specific agonist of NMDARs, has been found to cause more damage to neurons in the presence of group I mGluR agonists. On the other hand, agonists of group II and III mGluRs reduce NMDAR activity. Group II and III possibly by reducing the activity of NMDARs. Metabotropic glutamate receptors are also thought to affect
dopaminergic and
adrenergic neurotransmission.
Role in plasticity Like other
glutamate receptors, mGluRs have been shown to be involved in
synaptic plasticity They participate in
long term potentiation and
long term depression, and they are removed from the synaptic membrane in response to
agonist binding. In addition, manipulating mGluRs can be useful in treating some conditions. For example, clinical trial suggested that an mGlu2/3 agonist, LY354740, was effective in the treatment of
generalized anxiety disorder. Also, some researchers have suggested that activation of mGluR4 could be used as a treatment for
Parkinson's disease. Most recently, Group I mGluRs, have been implicated in the pathogenesis of
Fragile X, a type of
autism, and a number of studies are currently testing the therapeutic potential of drugs that modify these receptors. There is also growing evidence that group II metabotropic glutamate receptor agonists may play a role in the treatment of schizophrenia. Schizophrenia is associated with deficits in cortical inhibitory interneurons that release GABA and synaptic abnormalities associated with deficits in NMDA receptor function. These inhibitory deficits may impair cortical function via cortical disinhibition and asynchrony. The drug
LY354740 (also known as
Eglumegad, an mGlu
2/
3 agonist) was shown to attenuate physiologic and cognitive abnormalities in animal and human studies of NMDA receptor antagonist and
serotonergic hallucinogen effects, supporting the subsequent clinical evidence of efficacy for an mGluR2/3 agonist in the treatment of schizophrenia. The same drug has been shown to interfere in the
hypothalamic–pituitary–adrenal axis, with chronic oral administration of this drug leading to markedly reduced baseline
cortisol levels in bonnet macaques (
Macaca radiata); acute infusion of
LY354740 resulted in a marked diminution of
yohimbine-induced
stress response in those animals.
LY354740 has also been demonstrated to act on the
metabotropic glutamate receptor 3 (GRM3) of human
adrenocortical cells, downregulating
aldosterone synthase,
CYP11B1, and the production of
adrenal steroids (i.e.
aldosterone and
cortisol). ==History==