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Glutamic acid

Glutamate receptors are transmembrane receptors located primarily on the membranes of neuronal cells. These receptors bind the neurotransmitter glutamate.

Introduction

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Glutamate receptors are present in large numbers in the central nervous system, but are also found in many other areas of the body. These receptors are responsible for the glutamate mediated post-synaptic excitation of neural cells, and are important for memory formation and learning. Furthermore, glutamate receptors are implicated in the pathologies of a great number of neurodegenerative diseases.

Types of glutamate receptors

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Glutamate receptors can be divided into two groups according to the mechanism by which their activation gives rise to a postsynaptic current[1]. Ionotropic glutamate receptors (iGluRs) form the ion channel pore that activates when glutamate binds to the receptor. Metabotropic glutamate receptors (mGluRs) indirectly activate ion-channels on the plasma membrane through a signaling cascade that involves G proteins. Ionotropic receptors tend to be quicker in relaying information but metabotropic are associated with a more prolonged stimulus. This is due to the usage of many different messengers to carry out the signal but since there is a cascade, just one activation of a G-protein can lead to multiple activations. Glutamate receptors are usually not specifically geared towards glutamate exclusively as the ligand and sometimes even requires another agonist.

There are many specific subtypes of glutamate receptors, and it is customary to refer to primary subtypes by a chemical which binds to it more selectively than glutamate. The research, though, is ongoing as subtypes are identified and chemical affinities measured. There are several compounds which are routinely used in glutamate receptor research and associated with receptor subtypes:

Type Name Agonist(s)
ionotropic NMDA receptor NMDA
ionotropic Kainate receptor Kainate
ionotropic AMPA receptor AMPA
metabotropic mGluR L-AP4, ACPD, L-QA[2]

Metabotropic glutamate receptors are all named mGluR# and are further broken down into three groups:

Group # Receptors Effect
1 mGluR1

mGluR5

Increase in Ca2+ concentration in the cytoplasm.

Release of K+ from the cell by activating K+ ionic channels

2 mGluR2

mGluR3

Inhibition of adenylyl cyclase causing shut down of the cAMP-dependent pathway and therefore decreasing amount of cAMP
3 mGluR4

mGluR6

mGluR7

mGluR8

Activation of Ca2+ channels, allowing more Ca2+ to enter the cell[3]


Structure/Mechanism

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Glutamate receptors exist primarily in the central nervous system. These receptors can be found on the dendrites of post-synaptic cells and bind to glutamate released into the synaptic cleft by pre-synaptic cells. The glutamate binds to the extracellular portion of the receptor and provokes a response, however the various types of receptors can produce different responses.[4]


Ionotropic Glutamate Receptors

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All ionotropic glutamate receptors are ligand-gated nonselective cation channels which allow the flow of K+, Na+ and sometimes Ca2+ in response to glutamate binding. All produce excitatory post-synaptic current, but the speed and duration of the current is different for each type. NMDA receptors have an internal binding site for an Mg2+ ion creating a voltage dependant block which is removed by outward flow of positive current. [5] This causes NMDA receptors to have a slower and more prolonged post-synaptic current than AMPA/kainite receptors.

Metabatropic Glutamate Receptors

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Metabatropic glutamate receptors, which belong to the C family of G protein-coupled receptors are divided into three groups, with a total of eight sub-types. The mGluRs are composed of three distinct regions: the extracellular region, the transmembrane region, and the intracellular region. [6] The extracellular region is composed of a Venus Flytrap (or VFT) module that binds glutamate, [7] and a cysteine-rich domain that is thought to play a role in transmitting the conformational change induced by ligand binding from in the VFT module to the transmembrane region. [6] The transmembrane region consists of seven transmembrane domains and connects the extracellular region to the intracellular region where G protein coupling occurs. [7] Glutamate binding to the extracellular region of an mGluR causes G proteins bound to the intracellular region to be phosphorylated, affecting multiple biochemical pathways and ion channels in the cell. [8] Because of this, mGluRs can both increase or decrease the exitability of the post synaptic cell, thereby causing a wide range of physiological effects.

Function

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Glutamate is the most prominent neurotransmitter in the body,[9] being present in over 50% of nervous tissue. Glutamate was initially discovered to be a neurotransmitter following insect studies in the early 1960s. The primary glutamate receptor is specifically sensitive to N-Methyl-D-Aspartate (NMDA), which causes direct action of the central pore of the receptor, an ion channel, to drive the neuron to depolarize. Depolarization will trigger the firing, or action potential of the neuron, therefore NMDA is excitatory.[9] One of the major functions of glutamate receptors appears to be the modulation of synaptic plasticity; a property of the brain thought to be vital for memory and learning. Both metabotropic and ionotropic glutamate receptors have been shown to have an effect on synaptic plasticity. [10] An increase or decrease in the number of ionotropic glutamate receptors on a post-synaptic cell may lead to long-term potentiation or long-term depression of that cell, respectively. [11] [12] Additionally, metabotropic glutamate receptors may modulate synaptic plasticity by regulating post-synaptic protein synthesis through second messenger systems. [13]


Genetics

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Due to the diversity of glutamate receptors, their subunits are encoded by numerous gene families. Sequence similarities between mammals show a common evolutionary origin for many mGluR and all iGluR genes.[14] As recently researched, there is complete conservation of reading frames and splice sites of GluR genes between chimpanzees and humans, suggesting no gross structural changes after humans diverged from the human-chimpanzee common ancestor. However, there is possibility that two human-specific "fixed" amino acid substitutions, in GRIN3A and R727H, are specifically associated with human brain function.[15]
Glutamate receptor subunits and their genes[16]:

Receptor Family Subunit Gene Chromosome (human) GenEMBL# (Mouse) GenEMBL# (Rat) GenEMBL# (Human)
AMPA GluR1 GRIA1 5q33 X57497 X17184 I57354
AMPA GluR2 GRIA2 4q32-33 X57498 M85035 A46056
AMPA GluR3 GRIA3 Xq25-26 M85036 X82068
AMPA GluR4 GRIA4 11q22-23 M36421 U16129
Kainate GluR5 GRIK1 21q21.1-22.1 X66118 M83560 U16125
Kainate GluR6 GRIK2 6q16.3-q21 D10054 X11715 U16126
Kainate GluR7 GRIK3 1p34-p33 M83552 U16127
Kainate KA-1 GRIK4 11q22.3 X59996 S67803
Kainate KA-2 GRIK5 19q13.2 D10011 Z11581 S40369
NMDA NR1 GRIN1 9q34.3 D10028 X63255 X58633
NMDA NR2A GRIN2A 16p13.2 D10217 D13211 U09002
NMDA NR2B GRIN2B 12p12 D10651 M91562 U28861
NMDA NR2C GRIN2C 17q24-q25 D10694 D13212
NMDA NR2D GRIN2D 19q13.1qter D12822 D13214 U77783
NMDA NR3A GRIN3A L34938

So far, no genetic diseases in humans have been linked to mutations of any of the glutamate receptor subunit genes. However, a specific genotype of human GluR6 was discovered to have a slight influence on the age of onset of Huntington's disease.[17] Antibodies to glutamate receptor subunit genes accompany various neurological disorders (e.g. GluR3 in Rasmussen's encephalitis[18] and GluR2 in nonfamilial olivopontocerebellar degeneration[19]), but the exactly role of antibodies in disease manifestation is still not entirely known.[20]


Pathology

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Excitotoxicity

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Overstimulation of glutamate receptors causes neuronal degradation and death through a process called excitotoxicity. Excessive glutamate, or excitotoxins acting on the same glutamate receptors, overactivate glutamate receptors, causing high levels of calcium ions (Ca2+) to influx into the postsynaptic cell.[21] High Ca2+ concentrations activate a cascade of cell degradation processes involving proteases, lipases, nitric oxide synthase, and a number of enzymes that damage cell structures often to the point of cell death.[22] Ingestion or exposure to excitotoxins that act on glutamate receptors can induce excitotoxicity and cause toxic effects on the central nervous system.[23]

Neurodegeneration

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In the case of traumatic brain injury or cerebral ischemia (e.g. cerebral infarction or hemorrhage), acute neurodegeneration may spread to proximal neurons through two processes. Hypoxia and hypoglycemia trigger bioenergetic failure, decreasing ion concentration gradients across the plasma membrane. Depolarization increases synaptic release of glutamate[24] and reversed glutamate transport (efflux) in affected neurons and astrocytes[25]. In addition, neuronal death releases cytoplasmic glutamate outside of the ruptured cell.[25] These two forms of glutamate release cause a continual domino effect of excitotoxic cell death and further increased extracellular glutamate concentrations.

Neurogenerative Diseases

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Glutamate receptors’ significance in exitotoxicity links it to many neurogenerative diseases. Conditions such as exposure to excitotoxins, old age, congenital predisposition, and brain trauma can trigger glutamate receptor activation and ensuing excitotoxic neurodegeneration. This damage to the central nervous system propagates symptoms associated with a number of diseases.[26]

Neurogenerative diseases thought to be mediated (at least in part) through stimulation of glutamate receptors [27]:

Current Research

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Glutamate receptors have been found to have an influence in ischemia/stroke, seizures, Parkinson's Disease, Huntington's Disease, and aching.[28] As mentioned in the pathology section, almost every disease involving glutamate receptors have very similar if not identical pathways, differing slightly only in the area in the brain where the issue occurs. The following explores some of the treatments currently being proposed by targeting the glutamate receptor pathway.

Ischemia

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It has been observed that during ischemia, the brain has an unnaturally high concentration of extracellular glutamate. [29] This is linked to an inadequate supply of ATP which drives the glutamate transport levels that keep the concentrations of glutamate in balance.[30] This usually leads to an excessive activation of glutamate receptors, which may lead to neuronal injury. After this over exposure, the post synaptic terminals tend to keep glutamate around for long periods of time which result in a difficulty in depolarizing.[30] Antagonists for NDMA and AMPA receptors seem to have a large benefit, with more aid the sooner it is administered after onset of the neural ischemia. [23]

Seizures

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There has been some discovery about the role of glutamate receptors in epilepsy. NMDA and metabotropic types have been found to induce epileptic convulsions. Using rodent models, labs have found that the introduction of antagonists to these glutamate receptors help counteract the epileptic symptoms. [31] Since glutamate is a ligand for ligand-gated ion channels, the binding of this neurotransmitter will open gates and increase sodium and calcium conductance. These ions play an integral part in the causes of seizures. Group 1 metabotropic glutamate receptors (mGlu1 and mGlu5) are the primary cause of seizing so applying an antagonist to these receptors helps in preventing convulsions.[32]

Parkinson's Disease

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Late onset neurological disorders like Parkinson's disease have partial reliance on endogenous glutamate binding NMDA and AMPA glutamate receptors. [23] Invitro spinal cord cultures with glutamate transport inhibitors led to degeneration of motoneurons which was counteracted by some AMPA receptor antagonists like GYKI 52466.[23] Research also suggests that the metabotropic glutamate receptor, mGlu4, is directly involved in movement disorders associated with the basal ganglia through selectively modulating glutamate in the striatum. [33]

Huntington's Disease

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In addition to similar mechanisms causing Parkinson's Disease in respect to NMDA or AMPA receptors, Huntington's disease was also proposed to exhibit metabolic and mitochondrial deficiency which exposes striatal neurons to over activation of the NMDA receptor to dangerous levels.[23] There has been a proposition of using folic acid as a possible treatment for Huntington's due to the inhibition it exhibits on homocysteine which increases vulnerability of nerve cells to glutamate.[34] This could decrease the effect that the glutamate has on glutamate receptors and reduce cell response to a safer level, not reaching excitotoxicity.

Aching

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Hyperalgesia is directly involved with spinal NMDA receptors. Antagonizing NMDA in a clinical setting produces side effects not fit for mass consumption although more research is being done in intrathecal administration.[23] Since the spinal NMDA receptors are what links the area of pain to the brain's pain processing center, the thalamus, these glutamate receptors are a prime target for treatment. One proposed way to cope with the pain is actually subconsciously through the visualization technique.[30]

Diabetes

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Diabetes is a particular case because it is influenced by glutamate receptors present outside of the central nervous system, and it also influences glutamate receptors in the central nervous system. Diabetes mellitus, an endocrine disorder, induces cognitive impairment and defects of long-term potential in the hippocampus, interfering with synaptic plasticity. Defects of long-term potential in the hippocampus are due to abnormal glutamate receptors, specifically the malfunctioning NMDA glutamate receptors during early stages of the disease.[35] Research is being done to address the possibility of using hyperglycaemia and insulin to regulate these receptors and restore cognitive functions. Pancreatic islets regulating insulin and glucagon levels also express glutamate receptors.[36] It is possible to treat diabetes via glutamate receptor antagonists, but not much research has been done. The difficulty of modifying peripheral GluR without having detrimental effects on the central nervous system, which is saturated with GluR, may be the cause of this.

Effects Outside the Nervous System

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Glutamate receptors are thought to be responsible for the reception and transduction of umami taste stimuli. Taste receptors of the T1R family, belonging to the same class of GPCR as metabotropic Glutamate Receptors are involved. Additionally, the mGluRs as well as ionotropic glutamate receptors in neural cells have been found in taste buds and may contribute to the umami taste. [37] Numerous ionotropic glutamate receptor subunits are expressed by heart tissue, but their specific function is still unknown. Western blots, northern blots confirmed the presence of iGluRs in cardiac tissue. Immunohistochemistry localized them to cardiac nerve terminals, ganglia, conducting fibers, and some myocardiocytes.[38] Glutamate receptors are also expressed in pancreatic islet cells. [39] AMPA iGluRs modulate the secretion of insulin and glucagon in the pancreas, opening the possibility of treatment of diabetes via glutamate receptor antagonists.[40][41] Small unmyelinated sensory nerve terminals in the skin also express NMDA and non-NMDA receptors. Subcutaneous injections of receptor blockers in rats successfully analgesized skin from formalin-induced inflammation, raising possibilities of targetting peripheral glutamate receptors in the skin for pain treatment.[42]

Conclusion

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Like many things in the biological world, not everything about glutamate receptors has been discovered. Although the enigmatic nature of such a receptor plagues researchers, the current strides being taken in an attempt to aid many ailments caused by glutamate receptors have been productive. If breakthroughs can be researched and a successful clinical treatment developed, many of the debilitating issues rampant in society today could be remedied or relieved of symptoms. Due to the similar nature of each disease, a cure in Huntington's Disease may also cure or at least provide great insight into curing Parkinson's. Since glutamate receptors are such a large part of so many conditions, adequate research must be invested towards finding ways to regulate the response or binding of glutamate to glutamate receptors.

References

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