Introduction
Glutamate receptors are found on the membranes of cells that make up the nervous system. Glutamate is an amino acid that is found in large numbers in the body of a human being owing to its role in the assembly of proteins. It moreover serves as a neurotransmitter and is found in large numbers in the nervous system. Glutamate receptors enable the excitation of neural cells and are therefore very pivotal in neural communication. They are also associated with a number of degenerative diseases of the nervous system. The essay seeks to develop an insight into the diversity of functions and structure of glutamate receptors.
Functions of Glutamate Receptors
Ionotropic and metabotropic glutamate receptors play a vital role in synaptic transmission in the mammalian brain. They also play a role in taste perception. Glutamate makes 50 percent of the nervous tissue. It is one of the most important neurotransmitters in the body. It was first discovered in an insect body. Glutamate receptors are named after the agonists that bind to them with high specificity. These glutamate receptors are AMPA (alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate) and NMDA (N-Methyl-D-Aspartate). Its main role appears to be inclined to the regulation of synaptic plasticity. This is a very crucial aspect of memory and learning processes. Increase or decrease in a number of ionotropic glutamate receptors- a type of glutamate receptors on postsynaptic cells result in protracted depression or potentiation of that particular cell. Metabotropic glutamate receptors are known to regulate postsynaptic protein synthesis with the help of a second messenger. Current research implicates glutamate receptors to be present in the central nervous system glial cells and the neurons (Masu 1991, p. 762). They are linked to modulation of gene expression in glial cells when they proliferate and also the differentiation of glial precursor cells during the development of the brain.
Types of Glutamate Receptors
Glutamate receptors are divided into ionotropic glutamate receptors and metabotropic glutamate receptors. This classification is based on the mechanism by which their activation gives rise to postsynaptic current. Metabotropic glutamate receptors indirectly activate ion channels present on the plasma membrane by G-proteins signal cascade. Ionotropic receptors serve to quickly relay information whereas metabotropic glutamate receptors relay information after a protracted period of time relative to the ionotropic type (Abe 1992, p. 13362). This is occasioned by the use of myriad messengers to carry out signal transduction. However, because there is a cascade, activation of a G-protein can give rise to a number of activations. Glutamate receptors also do require other agonists. There are a number of glutamate receptors subtypes. The primary subtypes are normally named depending on the chemicals that selectively bind to them relative to glutamate. It is worth noting that there are ongoing researches aimed at identifying more subtypes. These researches also encompass the chemical affinities of these subtypes. Ionotropic glutamate receptors have 3 glutamate receptor families namely the NMDA receptor family, kainate receptor family, and AMPA receptor family. Its agonists comprise NMDA, Kainate, and AMPA. The metabotropic glutamate receptors have a mGluR receptor family with L-AP4, ACPD, and L-QA as the agonists. Because of glutamate receptor diversity, encoding of their subunits is carried out by many gene families. A bigger percentage of mammals possess similar ionotropic glutamate receptors genetic makeup hence a gesture that they share a common origin. Most of the primates and human beings’ GluR genes reading frames and splice sites have complete conservation. This shows that there have been very minimal structural changes after the divergence of humans from human-chimpanzee shared ancestry.
Ionotropic receptors
AMPA receptor family of the ionotropic glutamate receptors has 4 subunits namely GluR I, GluR II, GluR III, and GluR IV. GluR I is encoded by GRIA 1 gene found on human chromosome 5q33; GluR II is encoded by GRIA2 found on human chromosome 4q32-33; GluR III is encoded for by GRIA3 found on human chromosome xq25-26, and GluR IV is encoded for by GRIA4 found on human chromosome 11 q22-23. The Kainate receptor has 6 subunits namely GluR V, GluR VI, GluR VII, KA-1, and KA-2. The GluR V subunit is encoded by GRIK1 found on human chromosome 21q21. 1-22.1; GluR VI are encoded by GRIK2 found on human chromosome 6q16.3-q21; the GluR VII sub unit is encoded GRIK3 found on human chromosome 1 p34-p33; KA-1 and KA-2 sub units are encoded by GRIK4 and GRIK5 genes found on human chromosomes 11 q22.3 and 19q13.2 respectively. NMDA receptor family comprises NR1, NR2A, NR2B, NR2C, NR2D, NR3A, and NR3B sub units. NR1 sub units are encoded for by GRIN1 gene found on 9q34.3 human chromosome; NR2A is encoded on GRIN2A gene found on 16p 13.2 human chromosome; NR2B are encoded on GRIN2B found on 12p12 human chromosome; NR2C sub units are encoded for on GRIN2C gene found on 17 q24-q25 on a human chromosome; NR2D sub units are encoded on GRIN2D genes found on 19q13.1qter; NR3A and NR3B are encoded on genes GRIN3A and GRIN3B found on human chromosomes 9q31.1 and 19 p13.3 respectively (LaFerla 2002, p. 863).
Metabotropic receptors
Metabotropic receptors are divided into 3 groups. The first group of metabotropic glutamate receptors is composed of mGluR1 and mGluR 5 receptor families which are encoded by GRM1 and GRM5 genes respectively. They are found on human chromosomes 6q24 and 11q14.3. The mGluR1 increases the concentration of calcium ions in the cytoplasm whereas mGluR5 helps in the release of potassium ions from the cells when they activate potassium ionic channels. Group 2 metabotropic glutamate receptors are made up of mGluR2 and mGluR3 receptor families encoded by GRM2 and GRM3 genes found on human chromosome 3p21.2 and 7 q 21.1-q21.2 respectively. The group 2 metabotropic receptors play a role in the inhibition of adenylyl cyclase that prompts the shut down of cAMP-dependent pathways thereby decreasing the amount of cAMP. Group 3 that majorly consists of mGluR4, mGluR6, mGluR7, and mGluR8 activates calcium ion channels. This enables more calcium ions to enter the cell. The mGluR4 and mGluR6 are encoded for by GRM4 and GRM6 genes found on human chromosomes 6p21.3 and 5q35 respectively. The mGluR7 and mGluR8 are encoded by GRM7 and GRM8 genes found on human chromosomes 3p26-p25 and 7q31.3 – q 32.1 respectively (Pin 1995, p.10).
Structure and Mechanism of Ionotropic and Metabotropic glutamate receptors
Glutamate receptors are predominantly found in the central nervous system. They can often be found on postsynaptic cells dendrites. The pre-synaptic cells release glutamate into the synaptic cleft which then binds to the receptors. Glutamate receptors are also found in glial cells of the brain and spinal cord and also in cells that support axons to make the myelin sheath. It is the extracellular region of the receptor where glutamate binds to and in the process initiates a response. However, different kinds of receptors initiate different responses. With the exception of NMDA, both ionotropic and metabotropic glutamate receptors are normally present on glial cells that have been cultured. Glial cell opening is triggered by glutamate. Cells respond to this opening by activating second messengers. The second messengers basically regulate the expression of genes. The whole process results in the production of neuroactive compounds. Brain slices implicate glutamate receptors in in-vivo ubiquitous expression of brain glial cells and cells that form the myelin sheath. This property makes glutamate receptors of glial origin very crucial in the development of glial cells.
Ionotropic glutamate receptors
They are nonselective channels that facilitate the flow of potassium, sodium and at times calcium ion that occurs following the binding of glutamate to the receptor. When glutamate bind to glutamate receptors, the action of the central pore of the receptor has normally stimulated the agonist. The central pore of the receptor does act as the ion channel. It facilitates ion flow thereby causing excitatory postsynaptic current (EPSC). The current depolarizes. All ionotropic glutamate receptors produce EPSC. NMDA receptor opening is largely dependent on EPSC produced by AMPA receptors. NMDA receptor membrane can allow for in and out movement of calcium ions. The calcium ion is very important in gene regulation in the nervous system as its flow through NMDA receptors causes both LTD and LTP.
Metabotropic
Metabotropic glutamate receptors have 3 distinct regions namely extracellular, transmembrane, and intracellular regions. Venus flytrap and cysteine-rich domain are the major components of the extracellular region. They bind to the glutamate and transmit conformational change mediated by ligand binding respectively (Hollmann 1994, p.35). Transmembrane has 7 transmembrane domains. They connect the extracellular region to the intracellular region where the coupling of G- proteins takes place. The binding of glutamate to the extracellular region of glutamate metabotropic receptor enables for phosphorylation of G- proteins bound to the intracellular region. G- protein phosphorylation affect a number of biochemical pathways and ion channels in the cells. Owing to these properties, metabotropic glutamate receptors either decrease or increase the ability of postsynaptic cells to be excited. This brings into play a number of physiological effects.
Physiological Effects glutamate receptors found outside the CNS
Glutamate receptors have been associated with umami taste stimuli reception and transduction. T1R family taste receptors belong to GPCR class as mGluRs. The mGluRs and ionotropic metabotropic receptors found in the cells of the nervous system are found in taste buds. A number of ionotropic glutamate receptor subunits expressed by heart tissue functions have not been documented. The presence of ionotropic glutamate receptors in the tissues of the heart has been proven by the use of western and northern blots. Immunohistochemistry procedures have only managed to trace the presence of ionotropic glutamate receptors to the ganglion, nerve terminals of the heart, conducting fibers, and cardiocytes. Glutamate receptors expression also takes place in the islets of Langerhans in the pancreas. Of particular interest here are AMPA ionotropic glutamate receptors which regulate glucagon and insulin secretion in the pancreas. This shows that glutamate receptor antagonists can possibly be used to treat diabetes. The NMDA and non-NMDA receptor expression can also be expressed by the unmyelinated sensory nerve terminals found on the skin. Receptor blockers subcutaneously injected into rats are known to analgesic their skin from inflammations that result from their body contact with formalin. This raises the chances of using peripheral glutamate receptors for the treatment of pain on the skin (Lourenco 2000, p. 94).
Clinical significance of glutamate receptors
No study currently associate glutamate receptor subunit gene mutation with any disease incidence. Nevertheless, a human GluR6 genotype is thought to influence Huntington’s disease onset. Glutamate receptors subunits gene antibodies are associated with a number of neurological disorders like the GluR3 and Rasmussen’s encephalitis. However, the antibody’s definite role in the manifestation of these diseases is still not documented.
Excitotoxicity
Neurodegeneration does take place when the glutamate receptors are overstimulated. This basically occurs due to Excitotoxicity. When the protein glutamate is there in excess, glutamate receptors become overactive resulting in high levels of calcium ions in the postsynaptic cells. This consequently results in the activation of a cascade of cell degradation undertaken by proteases among other enzymes. Cell structure is destroyed. Excitotoxicity is normally occasioned by exposure to excitotoxins or ingestion as these contribute to central nervous system intoxication. Excitotoxicity of glutamate causes stress intracellular oxidative processes. Glutamate antiporter found in the proximal glial cells transports cysteine and glutamate into and out of the cell respectively. Excess concentrations of extracellular glutamate cause a decrease in cysteine. Decrease of the cysteine in the cell means the cell losses its ability to synthesize glutathione, which is an antioxidant. The unavailability of glutathione causes an increase in reactive oxygen species. This leads to the death of glial cells hence no processing of extracellular glutamate. Calcium ion concentrations influx leads to depletion of nitric oxide synthase. This also leads to nitric oxide over synthesis. Increased nitric oxide concentrations result in mitochondria damage hence depletion of energy reserves. An increase in nitric oxide concentration also results in the addition of oxidative stress to the neuron as this compound is also a reactive oxygen species (Mattson 2000, p. 222).
Neurodegeneration
Neurodegeneration may occur when a traumatic brain injury occurs. This may possibly spread to the proximal neurons through hypoxia and hypoglycemia which initiate bioenergetic failure. Mitochondria instantaneously halt the production of ATP energy. The sodium and potassium ATPases lose their ability to regulate the concentration of sodium and potassium ions across the plasma membrane. Transporters of glutamate across the plasma membrane that make use of sodium and potassium ion gradients, consequently, reverse glutamate transportation in affected neurons. Depolarization is also witnessed (Mattson 2000, p. 222). This serves to increase downstream synaptic release of glutamate.
Neurodegenerative complications
Excitotoxicity makes the glutamate receptors to be linked to neurodegenerative diseases. Exposure to substances like aspartame, advanced age, traumatic brain injury, and mother to child predisposition activates glutamate receptors thereby leading to excitotoxic brain lessoning. Damages to CNS lead to the emergence of symptoms that are associated with many diseases. Neurodegenerative diseases that are thought to be instigated by glutamate receptor stimulation include glaucoma; Alzheimer’s disease; Huntington’s disease; MELAS syndrome; Leber’s disease; AIDS dementia complex; Lateral sclerosis; hepatic encephalopathy; MERRF; hyperprolinemia; anxiety; Rett syndrome; Schizophrenia; and Parkinsonism (Mattson 2000, p.222).
Potential therapeutic applications
Ischemia
Ischemia is normally characterized by very high concentrations of extracellular glutamate relative to the conventional concentrations. This is attributed to the inadequacy of ATP supply. ATP facilitates glutamate transport levels. It, therefore, helps in glutamate concentrations balancing. A drop in ATP supply results in the over-activation of glutamate receptors and subsequently leads to neuronal injury. Because of the overexposure, glutamate will be kept around for a protracted period of time due to the activities of signals in postsynaptic cell terminals hence the occurrence of depolarization hitches. NMDA antagonists as well as AMPA receptors when given to Ischemia victims just when the disease manifests stand to benefit them.
Epileptic Seizures
Studies have implicated glutamate receptors to play a role in epilepsy onset. Ionotropic glutamate receptor NMDA and other metabotropic glutamate receptors play a role in the emergence of characteristics exhibited in epileptic victims. This was arrived at when lab rodents were used. The introduction of antagonists to glutamate receptors serves to counter the symptoms of epilepsy. The binding of the neurotransmitter to the glutamate increases the passage of sodium ions and potassium ions across the plasma membrane of the nerve cells. The ions are very crucial in causing seizures. The mGlu1 and mGlu5 metabotropic glutamate receptors are the major causes of seizures therefore the use of these receptors antagonists is a sure way of convulsion prevention.
Parkinsonism
Its late onset can partially be attributed to ionotropic glutamate receptors NMDA and AMPA. These receptors bind to glutamate endogenously. Spinal cord cultures having cells capable of altering synaptic transmission degenerate motor neurons counteracted by GYKI 52466. Metabotropic glutamate receptor mGlu4 contributes to movement problems associated with basal ganglia. They do this by selective modulation of glutamate.
Schizophrenia
Individuals with schizophrenia experience decreased mRNA expression in the NR2A subunit of metabotropic glutamate receptors. This occurs in the interneurons inhibitory subset found in the cerebral cortex. This has been necessitated by GABA upregulation. In the study, the NR2A subunit of the metabotropic glutamate receptors expressed in messenger RNA could not be detected in 50 percent of GABA neurons. It was found that there was a 50 percent decrease in the density of NR2A messenger RNA that expresses PV neurons. There was also a decrease in density of antibody labeled glutamatergic terminals compared to vesicular glutamate transporter that also registered a remarkable decrease. This study implied that the supply of nervous stimulation to glutamate receptors of inhibitory neurons containing PV leads to deficiency of schizophrenia in such cells. NR2A messenger RNA expression gets altered in the inhibitory neurons that contain calbindin. Research is currently being conducted that is focusing on the possibilities of using glutamate receptor antagonists in treating schizophrenia. Memantine, a non-selective receptor antagonist belonging to NMDA metabotropic glutamate receptors has been used as an add-on in clinical trials that emphasize the use of clozapine. Refractory schizophrenia victims have shown improvement after the use of GluR antagonists. Noncompetitive NMDA receptors have also been tested on laboratory rats. Studies have come to a consensus that specific antagonists can take part in the inhibition of the cortex and this subsequently prevents excessive transmission of nervous stimulation across the glutamate receptors symbolic with schizophrenia actions on GABAergic interneurons.
Diabetes Mellitus
A number of metabolic factors impact insulin secretion from the beta and alpha cells of the islets of Langerhans to regulate blood glucose levels. Somatostatin locally inhibits islets functions serve to reduce insulin and glucagon secretion by activation of Somatostatin receptors found in islets cells. Secretion of Somatostatin from delta cells is normally enhanced by high levels of glucose. It is thought that signaling of the glutamate enables the secretion of Somatostatin. Treatment of rat with either an AMPA, kainate or L-glutamate lead to stimulation of low glucose stimulation. Somatostatin inhibits the secretion of L-glutamate and glucagon from alpha cells (Satoshi 1993, p. 1276). Diabetes mellitus is a disorder of the endocrine system that leads to cognitive impairment. The glutamate receptors that influence the emergence and proliferation of diabetes are found outside the central nervous system. Research is currently being done to look if hyperglycemia and insulin can be used to regulate these glutamate receptors.
Conclusion
The ionotropic and metabotropic glutamate receptors are very diverse in terms of the structures and functions that they serve. Of much concern is the acceleration of the researches that are conducted towards coming up with a therapy that can help in curing neurodegenerative diseases that affect several people’s lives.
Reference list
Pin, J.P., Duvoisin, R., 1995, The metabotropic glutamate receptors: structure and functions. Neuropharmacology, 34:1-26.
Hollmann, M., Heinemann S, 1994, Cloned glutamate receptors. Annu Rev Neurosci, 17:31-108.
Lourenco, Neto, F., Schadrack, J., Berthele, A., Zieglgansberger, W., Tolle, T.R., Castro-Lopes JM., 2000, Differential distribution of metabotropic glutamate receptor subtype mRNAs in the thalamus of the rat. Brain Res, 854:93-105.
Masu, M., Tanabe, Y., Tsuchida. K., Shigemoto, R., Nakanishi, S., 1991, Sequence and expression of a metabotropic glutamate receptor. Nature, 349:760-765.
Abe, T., Sugihara, H., Nawa, H., 1992, Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction. J Biol Chem, 267:13361-13368.
Mattson, M.P., LaFerla, F.M., Chan, S.L., Leissring, M.A., Shepel, P.N., Geiger, J.D., 2000, Calcium signaling in the ER: its role in neuronal plasticity and neurodegenerative disorders. Trends Neurosci, 23:222-229.
LaFerla, F.M., 2002, Calcium dyshomeostasis and intracellular signaling in Alzheimer’s disease. Nat Rev Neurosci, 3:862-872.
Satoshi, G., Ynichi, H., Morsio, K., 1993, Altered cardiac adrenergic neurotransmission in streptozotocin-induced diabetic rats. Br J Pharmacol, 109:1276-1281.