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 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.
Glutamate receptors are implicated in a number of neurological conditions. Their central role in excitotoxicity and prevalence in the central nervous system has been linked or speculated to be linked to many neurodegenerative diseases, and several other conditions have been further linked to glutamate receptor gene mutations or receptor autoantigen/antibody activity.
Function
Glutamate
Glutamate is the most prominent neurotransmitter in the body, and is the main excitatory neurotransmitter, being present in over 50% of nervous tissue. Glutamate was initially discovered to be a neurotransmitter in insect studies in the early 1960s.
Glutamate is also used by the brain to synthesize GABA (γ-Aminobutyric acid), the main inhibitory neurotransmitter of the mammalian central nervous system. GABA plays a role in regulating neuronal excitability throughout the nervous system and is also directly responsible for the regulation of muscle tone in humans. Glutamate is the main excitatory and GABA the main inhibitory neurotransmitter in the mammalian cortex
Glutamate receptors Mammalian glutamate receptors are classified based on their pharmacology. However, glutamate receptors in other organisms have different pharmacology, and therefore these classifications do not hold. 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. An increase or decrease in the number of ionotropic glutamate receptors on a postsynaptic cell may lead to long-term potentiation or long-term depression of that cell, respectively. Additionally, metabotropic glutamate receptors may modulate synaptic plasticity by regulating postsynaptic protein synthesis through second messenger systems. Research shows that glutamate receptors are present in CNS glial cells as well as neurons. These glutamate receptors are suggested to play a role in modulating gene expression in glial cells, both during the proliferation and differentiation of glial precursor cells in brain development and in mature glial cells.
Glutamate receptors serve to facilitate the impact of the neurotransmitter glutamate in the central nervous system. These receptors are pivotal in excitatory synaptic transmission, synaptic plasticity, and neuronal development. They are vital for functions like learning, memory, and neuronal communication. Various subtypes of glutamate receptors, such as NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), and kainate receptors, have distinct roles in synaptic transmission and plasticity.
1. NMDA (N-methyl-D-aspartate) receptors: These receptors are involved in synaptic plasticity, learning, and memory. They are unique in that they require both glutamate and the co-agonist glycine to activate, and they are also voltage-dependent, meaning they only open when the postsynaptic membrane is depolarized. NMDA receptors are permeable to calcium ions, which can trigger intracellular signaling pathways that lead to changes in synaptic strength.
2. AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors: These receptors mediate the majority of fast excitatory synaptic transmission in the brain. They are permeable to sodium and potassium ions and are responsible for the rapid depolarization of the postsynaptic membrane that underlies the excitatory postsynaptic potential (EPSP). AMPA receptors are also involved in synaptic plasticity, particularly in the early stages of long-term potentiation (LTP).
3. Kainate receptors: These receptors are involved in both pre- and postsynaptic signaling and are thought to play a role in regulating synaptic transmission and plasticity. They are activated by the drug kainate and are permeable to both sodium and potassium ions. Kainate receptors are expressed in a variety of brain regions and are involved in processes such as sensory processing, motor control, and learning and memory.
Each subtype of glutamate receptor has a unique function and plays a crucial role in neuronal communication and plasticity.
Types Ionotropic glutamate receptors (iGluRs) form the ion channel pore that activates when glutamate binds to the receptor. Metabotropic glutamate receptors (mGluRs) affect the cell through a signal transduction cascade, and they may be primarily activating (mGlur1/5) or primarily inhibitory (mGlur2/3 and mGlur4/6/7/8). Ionotropic receptors tend to be quicker in relaying information, but metabotropic ones are associated with a more prolonged stimulus. The signalling cascade induced by metabotropic receptor activation means that even a relatively brief or small synaptic signal can have large and long-lasting effects, i.e. the system can have high "gain." NMDA receptor activation is particularly complex, as channel opening requires not only glutamate binding but also glycine or serine binding simultaneously at a separate site, and it also displays a degree of voltage dependence due to Zn2+ or Mg2+ binding in the pore. Furthermore, Ca2+ currents through the NMDA receptor modulate not just the membrane potential but act as an important second messenger system. The particular dynamics of the NMDAR allow it to function as a neural coincidence detector, and the NMDAR Ca2+ currents are critical in synaptic plasticity (LTP and LTD) and learning and memory in general.
Of the many specific subtypes of glutamate receptors, it is customary to refer to primary subtypes by a chemical that binds to it more selectively than glutamate. The research, however, is ongoing, as subtypes are identified and chemical affinities measured. Several compounds are routinely used in glutamate receptor research and associated with receptor subtypes:
Type Name Agonist(s) Antagonists ionotropic NMDA receptor NMDA Ketamine Kainate receptor KainateUBP-302 AMPA receptor AMPAPerampanel Group 1 metabotropic mGluR1, mGluR5DHPGLY-344,545Group 2 metabotropicmGluR2, mGluR3DCG-IVLY-341,495Group 3 metabotropicmGluR4, mGluR6, mGluR7, mGluR8L-AP4MMPIP (mGlur7)
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. Conservation of reading frames and splice sites of GluR genes between chimpanzees and humans is complete, suggesting no gross structural changes after humans diverged from the human-chimpanzee common ancestor. However, there is a possibility that two human-specific "fixed" amino acid substitutions, D71G in GRIN3A and R727H in GRIN3B, are specifically associated with human brain function.
Ionotropic Mammalian ionotropic glutamate receptor subunits and their genes: Mammalian receptor family Subunit (Old nomenclature) Gene Chromosome(human) AMPA GluA1 (GluR1) GRIA1 5q33 GluA2 (GluR2) GRIA2 4q32-33 GluA3 (GluR3) GRIA3 Xq25-26 GluA4 (GluR4) GRIA4 11q22-23 Kainate GluK1 (GluR5) GRIK1 21q21.1-22.1 GluK2 (GluR6) GRIK2 6q16.3-q21 GluK3 (GluR7) GRIK3 1p34-p33 GluK4 (KA-1) GRIK4 11q22.3 GluK5 (KA-2) GRIK5 19q13.2 NMDA GluN1(NR1) GRIN1 9q34.3 GluN2A (NR2A) GRIN2A 16p13.2 GluN2B (NR2B) GRIN2B 12p12 GluN2C (NR2C) GRIN2C 17q24-q25 GluN2D (NR2D) GRIN2D 19q13.1qter GluN3A (NR3A) GRIN3A 9q31.1 GluN3B (NR3B) GRIN3B 19p13.3
Metabotropic
Mammalian metabotropic glutamate receptors are all named mGluR# and are further broken down into three groups:
Group Receptor Gene Chromosome(human) Effect 1 mGluR1 GRM1 6q24 Increase in Ca2+ concentration in the cytoplasm. mGluR5 GRM5 11q14.3 Release of K+ from the cell by activating K+ ionic channels 2 mGluR2 GRM2 3p21.2 Inhibition of adenylyl cyclase causing shutdown of the cAMP-dependent pathwayAnd therefore decreasing amount of cAMP mGluR3 GRM3 7q21.1-q21.2 3 mGluR4 GRM4 6p21.3 Activation of Ca2+ channels, allowing more Ca2+ to enter the cell mGluR6 GRM6 5q35 mGluR7 GRM7 3p26-p25 mGluR8 GRM8 7q31.3-q32.1
In other (non mammalian) organisms, the classification and subunit composition of glutamate receptors is different.
Structure, mechanism and function
Glutamate receptors exist primarily in the central nervous system. These receptors can be found on the dendrites of postsynaptic cells and bind to glutamate released into the synaptic cleft by presynaptic cells. They are also present on both astrocytes and oligodendrocytes. Ionotropic and metabotropic glutamate receptors, with the exception of NMDA, are found on cultured glial cells, which can open in response to glutamate and cause cells to activate second messengers to regulate gene expression and release neuroactive compounds. Furthermore, brain slices show glutamate receptors are ubiquitously expressed in both developing and mature astrocytes and oligodendrocytes in vivo. Because of this, glial glutamate receptors are thought to be vital for glial cell development.
Ionotropic
Ionotropic glutamate receptors, by definition, are ligand-gated nonselective cation channels that allow the flow of K+, Na+ and sometimes Ca2+ in response to glutamate binding. (In C. elegans and Drosophila, invertebrate-specific subunits enable the flow of negative chloride ions rather than cations.) Upon binding, the agonist will stimulate direct action of the central pore of the receptor, an ion channel, allowing ion flow and causing excitatory postsynaptic current (EPSC). This current is depolarizing and, if enough glutamate receptors are activated, may trigger an action potential in the postsynaptic neuron. All produce excitatory postsynaptic 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-dependent block, which is removed by outward flow of positive current. Since the block must be removed by outward current flow, NMDA receptors rely on the EPSC produced by AMPA receptors to open. NMDA receptors are permeable to Ca2+, which is an important cation in the nervous system and has been linked to gene regulation. The flow of Ca2+ through NMDA receptors is thought to cause both long-term potentiation (LTP, of synapse efficacy) and long-term depression (LTD) by transducing signaling cascades and regulating gene expression.
Metabotropic