The metabotropic glutamate receptors, or mGluRs, are a type of
glutamate receptor
Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...
that are active through an indirect
metabotropic
A metabotropic receptor, also referred to by the broader term G-protein-coupled receptor, is a type of membrane receptor that initiates a number of metabolic steps to modulate cell activity. The nervous system utilizes two types of receptors: met ...
process. They are members of the
group C family of
G-protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
s, or GPCRs.
Like all glutamate
receptors
Receptor may refer to:
*Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a n ...
, mGluRs bind with
glutamate, an
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
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
Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered ...
,
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
, and the perception of
pain.
They are found in pre- and postsynaptic
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. ...
s in
synapses of the
hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
,
cerebellum,
and the
cerebral cortex
The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consistin ...
, as well as other parts of the
brain
A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a ve ...
and in peripheral tissues.
Like other
metabotropic receptor
A metabotropic receptor, also referred to by the broader term G-protein-coupled receptor, is a type of membrane receptor that initiates a number of metabolic steps to modulate cell activity. The nervous system utilizes two types of receptors: met ...
s, mGluRs have
seven transmembrane domains that span the cell membrane.
Unlike
ionotropic receptor
Ligand-gated ion channels (LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in res ...
s, metabotropic glutamate receptors are not
ion channels. Instead, they activate
biochemical cascade
A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor that ...
s, leading to the modification of other proteins, such as
ion channels.
This can lead to changes in the
synapse's excitability, for example by
presynaptic inhibition of
neurotransmission
Neurotransmission (Latin: ''transmissio'' "passage, crossing" from ''transmittere'' "send, let through") is the process by which signaling molecules called neurotransmitters are released by the axon terminal of a neuron (the presynaptic neuron), ...
, or modulation and even induction of postsynaptic responses.
A
dimeric organization of mGluRs is required for
signaling induced by
agonists.
Classification
Eight different types of mGluRs, labeled mGluR
1 to mGluR
8 ( 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 mGluR
7a and mGluR
7b.
Overview
Group I
The mGluRs in group I, including mGluR
1 and mGluR
5, are stimulated most strongly by the excitatory
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
analog
L-quisqualic acid.
Stimulating the receptors causes the associated
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. Acids trigger the release of bound calcium from cellular stores and the consequent increase in free cytosolic Ca2+, an essential step in ...
C to hydrolyze
phosphoinositide
Phosphatidylinositol (or Inositol Phospholipid) consists of a family of lipids as illustrated on the right, where red is x, blue is y, and black is z, in the context of independent variation, a class of the phosphatidylglycerides. In such molecul ...
phospholipids in the
cell's plasma membrane.
This leads to the formation of
inositol 1,4,5-trisphosphate (IP3) and
diacyl glycerol
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as su ...
. 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
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
calcium concentrations. The lipophilic
diacylglycerol
A diglyceride, or diacylglycerol (DAG), is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages. Two possible forms exist, 1,2-diacylglycerols and 1,3-diacylglycerols. DAGs can act as s ...
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.
Their action can be excitatory, increasing conductance, causing more glutamate to be released from the presynaptic cell, but they also increase
inhibitory postsynaptic potential
An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Incorporated; 2008. ...
s, or IPSPs.
They can also inhibit glutamate release and can modulate
voltage-dependent calcium channel
Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permea ...
s.
Group I mGluRs, but not other groups, are activated by
3,5-dihydroxyphenylglycine (DHPG),
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
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
, or cAMP, by activating a
G protein
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their a ...
that inhibits the enzyme
adenylyl cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
, which forms cAMP from
ATP.
[MRC (Medical Research Council)]
Glutamate receptors: Structures and functions.
, University of Bristol Centre for Synaptic Plasticity (2003). Retrieved January 20, 2008. 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 is a research drug which acts as a group-selective agonist for the group II metabotropic glutamate receptors (Metabotropic glutamate receptor 2, mGluR2/Metabotropic glutamate receptor 3, 3). It has potent neuroprotective and anticonvulsant ...
(DCG-IV) and
eglumegad
Eglumetad (INN; also known as 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 acti ...
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 (BINA, LS-193,571) is a research agent which acts as a potent and selective positive allosteric modulator for the group II metabotropic glutamate receptor subtype mGluR2.
In animal studies it showed anxiolytic and antipsychot ...
, have also now been developed.
LY-341,495
LY-341495 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 ( mGluR2/3).
It is used in scientific research in severa ...
and
MGS-0039
MGS-0039 is a drug that is used in neuroscientific research, which acts as a potent and selective antagonist for group II of the metabotropic glutamate receptors ( mGluR2/3). It produces antidepressant and anxiolytic effects in animal studies, ...
are drugs that act as a selective antagonist blocking both of the group II metabotropic glutamate receptors, mGluR
2 and mGluR
3.
RO4491533
RO-4491533 is a drug developed by Hoffmann-La Roche which acts as a potent and selective negative allosteric modulator for group II of the metabotropic glutamate receptors ( mGluR2/3), being equipotent at mGluR2 and mGluR3 but without activi ...
acts as a negative
allosteric modulator of mGluR
2 and mGluR
3.
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, mGluR
4 is located only in the brain, in locations such as the
thalamus
The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
,
hypothalamus
The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...
and
caudate nucleus
The caudate nucleus is one of the structures that make up the corpus striatum, which is a component of the basal ganglia in the human brain. While the caudate nucleus has long been associated with motor processes due to its role in Parkinson's d ...
. All mGluRs except mGluR
6 are thought to exist in the
hippocampus
The hippocampus (via Latin from Greek , ' seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, ...
and
entorhinal cortex
The entorhinal cortex (EC) is an area of the brain's allocortex, located in the medial temporal lobe, whose functions include being a widespread network hub for memory, navigation, and the perception of time.Integrating time from experience in the ...
.
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),
a type of ion channel-linked receptor that is central in a
neurotoxic
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specificall ...
process called
excitotoxicity
In excitotoxicity, nerve cells suffer damage or death when the levels of otherwise necessary and safe neurotransmitters such as glutamate become pathologically high, resulting in excessive stimulation of receptors. For example, when glutamate ...
. 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
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
Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...
neurotransmission.
Role in plasticity
Like other
glutamate receptors
Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous syste ...
, mGluRs have been shown to be involved in
synaptic plasticity
In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity. Since memories are postulated to be represented by vastly interconnected neural circuits ...
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 mGluR
1 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 mGlu
2/3 agonist, LY354740, was effective in the treatment of
generalized anxiety disorder
Generalized anxiety disorder (GAD) is a mental and behavioral disorder, specifically an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily function ...
.
Also, some researchers have suggested that activation of mGluR
4 could be used as a treatment for
Parkinson's disease
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
.
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
Eglumetad (INN; also known as 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 acti ...
, an mGlu
2/ 3 agonist) was shown to attenuate physiologic and cognitive abnormalities in animal and human studies of NMDA receptor antagonist and
serotonergic
Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron ''produces'' serotonin. A substance is ...
hallucinogen effects,
supporting the subsequent clinical evidence of efficacy for an mGluR
2/3 agonist in the treatment of schizophrenia.
The same drug has been shown to interfere in the
hypothalamic–pituitary–adrenal axis
The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland (a ...
, 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
Yohimbine (), also known as quebrachine, is an indole alkaloid derived from the bark of the African tree '' Pausinystalia johimbe''; also from the bark of the unrelated South American tree ''Aspidosperma quebracho-blanco''. Yohimbine is an α2 ...
-induced
stress response
The fight-or-flight or the fight-flight-or-freeze response (also called hyperarousal or the acute stress response) is a physiological reaction that occurs in response to a perceived harmful event, attack, or threat to survival. It was first des ...
in those animals.
LY354740 has also been demonstrated to act on the
metabotropic glutamate receptor 3
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 lo ...
(GRM3) of human
adrenocortical cells, downregulating
aldosterone synthase
Aldosterone synthase, also called steroid 18-hydroxylase, corticosterone 18-monooxygenase or P450C18, is a steroid hydroxylase cytochrome P450 enzyme involved in the biosynthesis of the mineralocorticoid aldosterone and other steroids. The enzyme ...
,
CYP11B1, and the production of
adrenal
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...
steroids (i.e.
aldosterone and
cortisol).
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 phosphate
Inositol phosphates are a group of mono- to hexaphosphorylated inositols. They play crucial roles in diverse cellular functions, such as cell growth, apoptosis, cell migration, endocytosis, and cell differentiation.
The group comprises:
* inosito ...
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.
References
Further reading
*
*
*
External links
*
{{Metabotropic glutamate receptor modulators
Metabotropic glutamate receptors
Protein domains
Protein families