Metabotropic glutamate receptor
Encyclopedia
Glutamate receptor
Glutamate receptors are synaptic receptors located primarily on the membranes of neuronal cells. Glutamate is one of the 20 amino acids used to assemble proteins and as a result is abundant in many areas of the body, but it also functions as a neurotransmitter and is particularly abundant in the...
that are active through an indirect metabotropic
Metabotropic receptor
Metabotropic receptor is a subtype of membrane receptors at the surface or in vesicles of eukaryotic cells.In the nervous system, based on their structural and functional characteristics, neurotransmitter receptors can be classified into two broad categories: metabotropic and ionotropic receptors...
process. They are members of the group C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
, mGluRs bind with glutamate, an amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
that functions as an excitatory neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
.
Function and structure
The mGluRs perform a variety of functions in the central and peripheral nervous systems: For example, they are involved in learningLearning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
, memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
, anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, and the perception of pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
. They are found in pre- and postsynaptic neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s in synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
s of the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
, cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
, and the cerebral cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
, as well as other parts of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
and in peripheral tissues.
Like other metabotropic receptor
Metabotropic receptor
Metabotropic receptor is a subtype of membrane receptors at the surface or in vesicles of eukaryotic cells.In the nervous system, based on their structural and functional characteristics, neurotransmitter receptors can be classified into two broad categories: metabotropic and ionotropic receptors...
s, mGluRs have seven transmembrane domains
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
that span the cell membrane. Like ionotropic receptors, metabotropic glutamate receptors are ion channel
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s. They activate biochemical cascade
Biochemical cascade
A biochemical cascade is a series of chemical reactions in which the products of one reaction are consumed in the next reaction. There are several important biochemical cascade reactions in biochemistry, including the enzymatic cascades, such as the coagulation cascade and the complement system,...
s, leading to the modification of other proteins, as for example ion channels. This can lead to changes in the synapse's
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
excitability, for example by presynaptic inhibition of neurotransmission
Neurotransmission
Neurotransmission , also called synaptic transmission, is the process by which signaling molecules called neurotransmitters are released by a neuron , and bind to and activate the receptors of another neuron...
, or modulation and even induction of postsynaptic responses.
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
| Family | Receptors | Gene | Mechanism | Function | Agonists & Activators | Antagonists | Synapse site |
|---|---|---|---|---|---|---|---|
| Group I | mGluR1 | GRM1 | Gq Gq alpha subunit Gq protein or Gq/11 is a heterotrimeric G protein subunit that activates phospholipase C . PLC in turn hydrolyzes Phosphatidylinositol 4,5-bisphosphate to diacyl glycerol and inositol triphosphate signal transduction pathway... , ↑Na+, ↑K+ Potassium channel In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes... , ↓glutamate |
|
|
mainly postsynaptic | |
| mGluR5 | GRM5 | Gq Gq alpha subunit Gq protein or Gq/11 is a heterotrimeric G protein subunit that activates phospholipase C . PLC in turn hydrolyzes Phosphatidylinositol 4,5-bisphosphate to diacyl glycerol and inositol triphosphate signal transduction pathway... , ↑Na+, ↑K+ Potassium channel In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes... , ↓glutamate |
|||||
| Group II | mGluR2 | GRM2 | Gi/G0 |
NMDA receptor The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function.... activity and risk of excitotoxicity Excitotoxicity Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are... |
Eglumegad Eglumegad 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.... Biphenylindanone A Biphenylindanone A is a research agent which acts as a potent and selective positive allosteric modulator for the group II metabotropic glutamate receptor subtype mGluR2....
|
|
mainly presynaptic |
| mGluR3 | GRM3 | Gi/G0 | |||||
| Group III | mGluR4 | GRM4 | Gi/G0 |
NMDA receptor The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function.... activity and risk of excitotoxicity Excitotoxicity Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are... |
|
mainly presynaptic | |
| 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 acidAmino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
analog L-quisqualic acid. Stimulating the receptors causes the associated enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
phospholipase
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...
C to hydrolyze phosphoinositide phospholipid
Phospholipid
Phospholipids are a class of lipids that are a major component of all cell membranes as they can form lipid bilayers. Most phospholipids contain a diglyceride, a phosphate group, and a simple organic molecule such as choline; one exception to this rule is sphingomyelin, which is derived from...
s in the cell's
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
plasma membrane. 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
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
, 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
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
for the activation of protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
.
These receptors are also associated with Na+ and K+ channels
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
. Their action can be excitatory, increasing conductance, causing more glutamate to be released from the presynaptic cell, but they also increase inhibitory postsynaptic potential
Inhibitory postsynaptic potential
An inhibitory postsynaptic potential is a synaptic potential that decreases the chance that a future action potential will occur in a postsynaptic neuron or α-motoneuron...
s, or IPSPs. They can also inhibit glutamate release and can modulate voltage-dependent calcium channel
Voltage-dependent calcium channel
Voltage-dependent calcium channels are a group of voltage-gated ion channels found in excitable cells with a permeability to the ion Ca2+...
s.
Group I mGluRs, but not other groups, are activated by 3,5-dihydroxyphenylglycine
Dihydroxyphenylglycine
-3,5-Dihydroxyphenylglycine or DHPG is a potent agonist of group I metabotropic glutamate receptors mGluR1 and mGluR5.DHPG was the first agonist shown to be selective for group I mGluRs...
(DHPG), a fact that 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 monophosphateCyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
, or cAMP, by activating a G protein
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
that inhibits the enzyme adenylyl cyclase, which forms cAMP from ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
. 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
Eglumegad
Eglumegad 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....
activate only group II mGluRs, while 2-amino-4-phosphonobutyrate (L-AP4) activates only group III mGluRs. Several subtype-selective positive allosteric modulators that activate only the mGlu2 subtype, such as Biphenylindanone A
Biphenylindanone A
Biphenylindanone A is a research agent which acts as a potent and selective positive allosteric modulator for the group II metabotropic glutamate receptor subtype mGluR2....
, have also now been developed.
LY-341,495
LY-341,495
LY-341,495 is a research drug developed by the pharmaceutical company Eli Lilly, which acts as a potent and selective orthosteric antagonist for the group II metabotropic glutamate receptors ....
is a drug that 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 located mostly 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 example, mGluR4 is located only in the brain, in locations such as the thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
and caudate nucleus
Caudate nucleus
The caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...
. All mGluRs except mGluR6 are thought to exist in the hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and entorhinal cortex
Entorhinal cortex
The entorhinal cortex is located in the medial temporal lobe and functions as a hub in a widespread network for memory and navigation. The EC is the main interface between the hippocampus and neocortex...
.
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 receptorsNMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
(NMDARs), a type of ion channel-linked receptor that is central in a neurotoxic
Neurotoxicity
Neurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
process called excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
. 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
N-Methyl-D-aspartic acid or N-Methyl-D-aspartate is an amino acid derivative which acts as a specific agonist at the NMDA receptor mimicking the action of glutamate, the neurotransmitter which normally acts at that receptor...
(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 mGluRs tend to protect neurons from excitotoxicity, possibly by reducing the activity of NMDARs.
Metabotropic glutamate receptors are also thought to affect dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
rgic and adrenergic
Adrenergic
An adrenergic agent is a drug, or other substance, which has effects similar to, or the same as, epinephrine . Thus, it is a kind of sympathomimetic agent...
neurotransmission.
Role in plasticity
Like other glutamate receptors, mGluRs have been shown to be involved in synaptic plasticitySynaptic plasticity
In neuroscience, synaptic plasticity is the ability of the connection, or synapse, between two neurons to change in strength in response to either use or disuse of transmission over synaptic pathways. Plastic change also results from the alteration of the number of receptors located on a synapse...
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
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
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 diseaseParkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
.
Most recently, Group I mGluRs, have been implicated in the pathogenesis of Fragile X, a type of autism
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...
, 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. An mGluR2/3 agonist was shown to attenuate physiologic and cognitive abnormalities in animal and human studies of NMDA receptor antagonist and serotonergic
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...
hallucinogen effects, supporting the subsequent clinical evidence of efficacy for an mGluR2/3 agonist in the treatment of schizophrenia.
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 phosphateInositol phosphate
Inositol phosphates are a group of mono- to polyphosphorylated inositols. They play crucial roles in diverse cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation.The group comprises:...
s. 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. In 1991 the first metabotropic glutamate receptor of the seven transmembrane domain family was cloned. More recent reports on ionotropic glutamate receptors able to couple to metabotropic transduction systems suggest that metabotropic responses of glutamate might not be limited to seven transmembrane domain metabotropic glutamate receptors.