Metabotropic glutamate receptor

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Metabotropic glutamate receptor dimer (Type 2) in ribbon representation 7epa mGluR2 homodimer inactive.png
Metabotropic glutamate receptor dimer (Type 2) in ribbon representation
L-Glutamic acid L-Glutaminsaure - L-Glutamic acid.svg
L-Glutamic acid

The metabotropic glutamate receptors, or mGluRs, are a type of glutamate receptor that are active through an indirect metabotropic process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. [1] Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatory neurotransmitter.

Contents

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. [2] They are found in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum, [3] and the cerebral cortex, as well as other parts of the brain and in peripheral tissues. [4]

Like other metabotropic receptors, mGluRs have seven transmembrane domains that span the cell membrane. [5] Unlike ionotropic receptors, metabotropic glutamate receptors are not ion channels. Instead, they activate biochemical cascades, leading to the modification of other proteins, such as ion channels. [6] This can lead to changes in the synapse's excitability, for example by presynaptic inhibition of neurotransmission, [7] or modulation and even induction of postsynaptic responses. [1] [4] [5] [8]

A dimeric organization of mGluRs is required for signaling induced by agonists. [9]

Classification

Eight different types of mGluRs, labeled mGluR1 to mGluR8 ( GRM1 to GRM8 ), are divided into groups I, II, and III. [1] [3] [4] [8] Receptor types are grouped based on receptor structure and physiological activity. [2] The mGluRs are further divided into subtypes, such as mGluR7a and mGluR7b.

Overview

Overview of glutamate receptors
FamilyReceptors [10] [11] GeneMechanism [10] FunctionAgonists & ActivatorsAntagonistsSynapse site
Group ImGluR1 GRM1 Gq, ↑Na+, [4] ↑K+, [4] ↓glutamate [8] mainly postsynaptic [14]
mGluR5 GRM5 Gq, ↑Na+, [4] ↑K+, [4] ↓glutamate [8]
Group IImGluR2 GRM2 Gi/G0 mainly presynaptic [14]
mGluR3 GRM3 Gi/G0
Group IIImGluR4 GRM4 Gi/G0 mainly presynaptic [14]
mGluR6 GRM6 Gi/G0
mGluR7 GRM7 Gi/G0
mGluR8 GRM8 Gi/G0

Group I

Quisqualic acid Quisqualic acid.svg
Quisqualic acid

The mGluRs in group I, including mGluR1 and mGluR5, are stimulated most strongly by the excitatory amino acid analog L-quisqualic acid. [4] [16] Stimulating the receptors causes the associated enzyme phospholipase C to hydrolyze phosphoinositide phospholipids in the cell's plasma membrane. [1] [4] [8] This leads to the formation of inositol 1,4,5-trisphosphate (IP3) and diacyl glycerol. Due to its hydrophilic character, IP3 can travel to the endoplasmic reticulum, where it induces, via fixation on its receptor, the opening of calcium channels increasing in this way the cytosolic calcium concentrations. The lipophilic diacylglycerol remains in the membrane, acting as a cofactor for the activation of protein kinase C.

These receptors are also associated with Na+ and K+ channels. [4] 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. [4] They can also inhibit glutamate release and can modulate voltage-dependent calcium channels. [8]

Group I mGluRs, but not other groups, are activated by 3,5-dihydroxyphenylglycine (DHPG), [14] a fact that is useful to experimenters because it allows them to isolate and identify them.

Group II and 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. [1] [3] [4] [17] These receptors are involved in presynaptic inhibition, [8] 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. [4]

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. [14] Several subtype-selective positive allosteric modulators that activate only the mGlu2 subtype, such as Biphenylindanone A, have also now been developed.

LY-341,495 and MGS-0039 are drugs that act as a selective antagonist blocking both of the group II metabotropic glutamate receptors, mGluR2 and mGluR3. [18] RO4491533 acts as a negative allosteric modulator of mGluR2 and mGluR3. [19]

Localization

Different types of mGluRs are distributed differently in cells. For example, one study found that Group I mGluRs are located mostly on postsynaptic parts of cells, while groups II and III are mostly located on presynaptic elements, [14] though they have been found on both pre- and postsynaptic membranes. [8]

Also, different mGluR subtypes are found predominantly in different parts of the body. For example, mGluR4 is located only in the brain, in locations such as the thalamus, hypothalamus and caudate nucleus. [20] All mGluRs except mGluR6 are thought to exist in the hippocampus and entorhinal cortex. [14]

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 (NMDARs), [12] [13] 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. [21]

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. [22] 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. [23] On the other hand, agonists of group II [24] and III mGluRs reduce NMDAR activity. [15]

Group II [25] and III [23] mGluRs tend to protect neurons from excitotoxicity, [15] [26] [27] possibly by reducing the activity of NMDARs.

Metabotropic glutamate receptors are also thought to affect dopaminergic and adrenergic neurotransmission. [28]

Role in plasticity

Like other glutamate receptors, mGluRs have been shown to be involved in synaptic plasticity [1] [8] and in neurotoxicity and neuroprotection. [29] [30]

They participate in long term potentiation and long term depression, and they are removed from the synaptic membrane in response to agonist binding. [17]

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. [31] 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. [32] Also, some researchers have suggested that activation of mGluR4 could be used as a treatment for Parkinson's disease. [33] Most recently, Group I mGluRs, have been implicated in the pathogenesis of Fragile X, a type of autism, [34] and a number of studies are currently testing the therapeutic potential of drugs that modify these receptors. [35] 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. [36] These inhibitory deficits may impair cortical function via cortical disinhibition and asynchrony. [37] 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, [38] [39] [40] [41] supporting the subsequent clinical evidence of efficacy for an mGluR2/3 agonist in the treatment of schizophrenia. [42] 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. [43] 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). [44]

History

The first demonstration that glutamate could induce the formation of molecules belonging to a major second messenger system was in 1985, when it was shown that it could stimulate the formation of inositol phosphates. [45] This finding allowed in 1987 to yield an explanation for oscillatory ionic glutamate responses and to provide further evidence for the existence of metabotropic glutamate receptors. [46] In 1991 the first metabotropic glutamate receptor of the seven transmembrane domain family was cloned. [47] More recent reports on ionotropic glutamate receptors able to couple to metabotropic transduction systems [48] [49] suggest that metabotropic responses of glutamate might not be limited to seven transmembrane domain metabotropic glutamate receptors.

Related Research Articles

<span class="mw-page-title-main">AMPA receptor</span> Transmembrane protein family

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic transmembrane receptor for glutamate (iGluR) and predominantly Na+ ion channel that mediates fast synaptic transmission in the central nervous system (CNS). It has been traditionally classified as a non-NMDA-type receptor, along with the kainate receptor. Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen. The GRIA2-encoded AMPA receptor ligand binding core (GluA2 LBD) was the first glutamate receptor ion channel domain to be crystallized.

<span class="mw-page-title-main">NMDA receptor</span> Glutamate receptor and ion channel protein found in nerve cells

The N-methyl-D-aspartatereceptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and predominantly Ca2+ ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and kainate receptors. Depending on its subunit composition, its ligands are glutamate and glycine (or D-serine). However, the binding of the ligands is typically not sufficient to open the channel as it may be blocked by Mg2+ ions which are only removed when the neuron is sufficiently depolarized. Thus, the channel acts as a “coincidence detector” and only once both of these conditions are met, the channel opens and it allows positively charged ions (cations) to flow through the cell membrane. The NMDA receptor is thought to be very important for controlling synaptic plasticity and mediating learning and memory functions.

In neurophysiology, long-term depression (LTD) is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer following a long patterned stimulus. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress.

In neuroscience, a silent synapse is an excitatory glutamatergic synapse whose postsynaptic membrane contains NMDA-type glutamate receptors but no AMPA-type glutamate receptors. These synapses are named "silent" because normal AMPA receptor-mediated signaling is not present, rendering the synapse inactive under typical conditions. Silent synapses are typically considered to be immature glutamatergic synapses. As the brain matures, the relative number of silent synapses decreases. However, recent research on hippocampal silent synapses shows that while they may indeed be a developmental landmark in the formation of a synapse, that synapses can be "silenced" by activity, even once they have acquired AMPA receptors. Thus, silence may be a state that synapses can visit many times during their lifetimes.

<span class="mw-page-title-main">Kainate receptor</span> Class of ionotropic glutamate receptors

Kainate receptors, or kainic acid receptors (KARs), are ionotropic receptors that respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from the algae Digenea simplex. They have been traditionally classified as a non-NMDA-type receptor, along with the AMPA receptor. KARs are less understood than AMPA and NMDA receptors, the other ionotropic glutamate receptors. Postsynaptic kainate receptors are involved in excitatory neurotransmission. Presynaptic kainate receptors have been implicated in inhibitory neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism.

<span class="mw-page-title-main">Glutamate receptor</span> Cell-surface proteins that bind glutamate and trigger changes which influence the behavior of cells

Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate is abundant in the human body, but particularly in the nervous system and especially prominent in the human brain where it is the body's most prominent neurotransmitter, the brain's main excitatory neurotransmitter, and also the precursor for GABA, the brain's main inhibitory neurotransmitter. Glutamate receptors are responsible for the glutamate-mediated postsynaptic excitation of neural cells, and are important for neural communication, memory formation, learning, and regulation.

<i>N</i>-Acetylaspartylglutamic acid Peptide neurotransmitter

N-Acetylaspartylglutamic acid is a peptide neurotransmitter and the third-most-prevalent neurotransmitter in the mammalian nervous system. NAAG consists of N-acetylaspartic acid (NAA) and glutamic acid coupled via a peptide bond.

Gliotransmitters are chemicals released from glial cells that facilitate neuronal communication between neurons and other glial cells. They are usually induced from Ca2+ signaling, although recent research has questioned the role of Ca2+ in gliotransmitters and may require a revision of the relevance of gliotransmitters in neuronal signalling in general.

<span class="mw-page-title-main">Metabotropic glutamate receptor 2</span> Mammalian protein found in humans

Metabotropic glutamate receptor 2 (mGluR2) is a protein that, in humans, is encoded by the GRM2 gene. mGluR2 is a G protein-coupled receptor (GPCR) that couples with the Gi alpha subunit. The receptor functions as an autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons.

<span class="mw-page-title-main">Metabotropic glutamate receptor 3</span> Mammalian protein found in humans

Metabotropic glutamate receptor 3 (mGluR3) is an inhibitory Gi/G0-coupled G-protein coupled receptor (GPCR) generally localized to presynaptic sites of neurons in classical circuits. However, in higher cortical circuits in primates, mGluR3 are localized post-synaptically, where they strengthen rather than weaken synaptic connectivity. In humans, mGluR3 is encoded by the GRM3 gene. Deficits in mGluR3 signaling have been linked to impaired cognition in humans, and to increased risk of schizophrenia, consistent with their expanding role in cortical evolution.

<span class="mw-page-title-main">Metabotropic glutamate receptor 5</span> Mammalian protein found in humans

Metabotropic glutamate receptor 5 is an excitatory Gq-coupled G protein-coupled receptor predominantly expressed on the postsynaptic sites of neurons. In humans, it is encoded by the GRM5 gene.

<span class="mw-page-title-main">Metabotropic glutamate receptor 7</span> Mammalian protein found in humans

Metabotropic glutamate receptor 7 is a protein that in humans is encoded by the GRM7 gene.

<span class="mw-page-title-main">HOMER1</span> Protein and coding gene in humans

Homer protein homolog 1 or Homer1 is a neuronal protein that in humans is encoded by the HOMER1 gene. Other names are Vesl and PSD-Zip45.

<span class="mw-page-title-main">Eglumetad</span> Chemical compound

Eglumetad is a research drug developed by Eli Lilly and Company, which is being investigated for its potential in the treatment of anxiety and drug addiction. It is a glutamate derived compound and its mode of action implies a novel mechanism.

The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms of schizophrenia linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.

<span class="mw-page-title-main">AMN082</span> Chemical compound

AMN082 is a selective metabotropic glutamate receptor 7 (mGluR7) allosteric agonist. It mimics the effect of glutamate. AMN082 is the first selective mGluR7 agonist and has expanded the potential array of research opportunities on the effects of mGluR7 in the central nervous system.

<span class="mw-page-title-main">Pomaglumetad</span> Drug, used as a treatment for schizophrenia

Pomaglumetad (LY-404,039) is an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3. Pharmacological research has focused on its potential antipsychotic and anxiolytic effects. Pomaglumetad is intended as a treatment for schizophrenia and other psychotic and anxiety disorders by modulating glutamatergic activity and reducing presynaptic release of glutamate at synapses in limbic and forebrain areas relevant to these disorders. Human studies investigating therapeutic use of pomaglumetad have focused on the prodrug LY-2140023, a methionine amide of pomaglumetad (also called pomaglumetad methionil) since pomaglumetad exhibits low oral absorption and bioavailability in humans.

<span class="mw-page-title-main">LY-379,268</span> Chemical compound

LY-379,268 is a drug that is used in neuroscience research, which acts as a potent and selective agonist for the group II metabotropic glutamate receptors (mGluR2/3).

<span class="mw-page-title-main">LY-487,379</span> Chemical compound

LY-487,379 is a drug used in scientific research that acts as a selective positive allosteric modulator for the metabotropic glutamate receptor group II subtype mGluR2. It is used to study the structure and function of this receptor subtype, and LY-487,379 along with various other mGluR2/3 agonists and positive modulators are being investigated as possible antipsychotic and anxiolytic drugs.

<span class="mw-page-title-main">Willardiine</span> Chemical compound

Willardiine (correctly spelled with two successive i's) or (S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione is a chemical compound that occurs naturally in the seeds of Mariosousa willardiana and Acacia sensu lato. The seedlings of these plants contain enzymes capable of complex chemical substitutions that result in the formation of free amino acids (See:#Synthesis). Willardiine is frequently studied for its function in higher level plants. Additionally, many derivates of willardiine are researched for their potential in pharmaceutical development. Willardiine was first discovered in 1959 by R. Gmelin, when he isolated several free, non-protein amino acids from Acacia willardiana (another name for Mariosousa willardiana) when he was studying how these families of plants synthesize uracilyalanines. A related compound, Isowillardiine, was concurrently isolated by a different group, and it was discovered that the two compounds had different structural and functional properties. Subsequent research on willardiine has focused on the functional significance of different substitutions at the nitrogen group and the development of analogs of willardiine with different pharmacokinetic properties. In general, Willardiine is the one of the first compounds studied in which slight changes to molecular structure result in compounds with significantly different pharmacokinetic properties.

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