Metabotropic glutamate receptor

Metabotropic glutamate receptor

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor which are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind to glutamate, an amino acid that functions as an excitatory neurotransmitter.

Function and structure

The mGluRs perform a variety of functions in the central and peripheral nervous systems: for example, they are involved in learning, memory, anxiety, and the perception of pain. They are found in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum, and the cerebral cortex, as well as other parts of the brain and in peripheral tissues.

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.

Classification

Eight different types of mGluRs, labeled mGluR1 to mGluR8 (to ), are divided into groups I, II, and III. Receptor types are grouped based on receptor structure and physiological activity. The mGluRs are further divided into subtypes, such as mGluR7a and mGluR7b.

Overview

Overview of glutamate receptors
Family Receptors Gene Mechanism
Group I mGluR1 GRM1 Gq, ↑Na+, ↑K+, ↓glutamate
mGluR5 GRM5 Gq, ↑Na+, ↑K+, ↓glutamate
Group II mGluR2 GRM2 Gi/G0
mGluR3 GRM3 Gi/G0
Group III mGluR4 GRM4 Gi/G0
mGluR6 GRM6 Gi/G0
mGluR7 GRM7 Gi/G0
mGluR8 GRM8 Gi/G0

Group I

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.

Group II & Group III

The receptors in group II, including mGluRs 2 and 3, and group III, including mGluRs 4, 6, 7, and 8, (with some exceptions) prevent the formation of cyclic adenosine monophosphate, or cAMP, by activating a G protein that inhibits the enzyme adenylyl cyclase, which forms cAMP from ATP. These receptors are involved in presynaptic inhibition, and do not appear to affect postsynaptic membrane potential by themselves. Receptors in groups II and III reduce the activity of postsynaptic potentials, both excitatory and inhibitory, in the cortex.

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.

Localization

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.

Roles

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, 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, 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.

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. and in neurotoxicity and neuroprotection.

They participate in long term potentiation and long term depression, and they are removed from the synaptic membrane in response to agonist binding.

Roles in disease

Since metabotropic glutamate receptors are involved in a variety of functions, abnormalities in their expression can contribute to disease. For example, studies with mutant mice have suggested that mutations in expression of mGluR1 may be involved in the development of certain types of cancer. 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.

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.

History

It was first suggested that mGluRs might exist in 1985, after it was noted that glutamate could stimulate phospholipase C through the activation of a receptor that did not belong to any of the ionotropic glutamate receptor families (NMDA, AMPA, or Kainate receptors). The suspicion that mGluRs existed was confirmed in 1987, and in 1991 the first mGluR was cloned.

References

External links

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