Like other metabotropic receptors, mGluRs have seven transmembrane domains that span the cell membrane. Unlike ionotropic receptors, metabotropic receptors are not directly linked to ion channels, but may affect them by activating biochemical cascades. In addition to producing excitatory and inhibitory postsynaptic potentials, mGluRs serve to modulate the function of other receptors (such as NMDA receptors), changing the synapse's excitability.
Metabotropic glutamate receptors can cause Ca2+ to be released from intracellular structures in which it is stored, such as the endoplasmic reticulum (ER). Activation of mGluRs causes the production of Inositol trisphosphate, which activates receptors on the ER that open Ca2+-permeable channels.
|Group I||mGluR1||GRM1||Gq, ↑Na+, ↑K+, ↓glutamate|
|mGluR5||GRM5||Gq, ↑Na+, ↑K+, ↓glutamate|
The mGluRs in group I, including mGluR1 and mGluR5, are stimulated most strongly by the excitatory amino acid analog L-quisqualic acid. Stimulating the receptors causes an associated phospholipase C molecule to hydrolyze phosphoinositide phospholipids in the cell's plasma membrane.
These receptors are also associated with Na+ and K+ channels. Their action can be excitatory, increasing conductance, causing more glutamate to be released from the presynaptic cell, but they also increase inhibitory postsynaptic potentials, or IPSPs. They can also inhibit glutamate release and can modulate voltage-dependent calcium channels.
Group I mGluRs, but not other groups, are activated by 3,5-dihydroxyphenylglycine (DHPG), a fact which is useful to experimenters because it allows them to isolate and identify them.
The chemicals 2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) and eglumegad activate only group II mGluRs, while 2-amino-4-phosphonobutyrate (L-AP4) activates only group III mGluRs. Several subtype-selective positive allosteric modulators have also now been developed which activate only the mGlu2 subtype, such as Biphenylindanone A.
LY-341,495 is a drug which acts as a selective antagonist blocking both of the group II metabotropic glutamate receptors, mGluR2 and mGluR3.
Different types of mGluRs are distributed differently in cells. For example, one study found that Group I mGluRs are mostly located on postsynaptic parts of cells while groups II and III are mostly located on presynaptic elements, though they have been found on both pre- and postsynaptic membranes.
Also, different mGluR subtypes are found predominantly in different parts of the body. For exaple, mGluR4 is located only in the brain, in locations such as the thalamus, hypothalamus and caudate nucleus. All mGluRs except mGluR6 are thought to exist in the hippocampus and entorhinal cortex.
It is thought that mGluRs play a role in a variety of different functions.
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, an agonist for 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 mGluRs tend to protect neurons from excitotoxicity, possibly by reducing the activity of NMDARs.
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. An mGluR2/3 agonist was shown to attenuate physiologic and cognitive abnormalities in the 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.
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