AMPA receptor
Encyclopedia
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...
-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...
transmission in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS). Its name is derived from its ability to be activated by the artificial glutamate analog AMPA
AMPA
AMPA is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate....
. The receptor was discovered by Tage Honore and colleagues at the School of Pharmacy in Copenhagen, and published in 1982 in the Journal of Neurochemistry. AMPARs are found in many 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 are the most commonly found receptor in the nervous system
Nervous system
The nervous system is an organ system containing a network of specialized cells called neurons that coordinate the actions of an animal and transmit signals between different parts of its body. In most animals the nervous system consists of two parts, central and peripheral. The central nervous...
. The AMPA receptor GluA2 (GluR2) tetramer was the first and currently only glutamate receptor ion channel to be crystallized.
Subunit Composition
AMPARs are composed of four types of subunits, designated as GluR1GRIA1
Glutamate receptor 1 is a protein that in humans is encoded by the GRIA1 gene.Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes...
, GluR2
GRIA2
Glutamate receptor 2 is a protein that in humans is encoded by the GRIA2 gene.- Function :Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes...
, GluR3
GRIA3
Glutamate receptor 3 is a protein that in humans is encoded by the GRIA3 gene.- Function :Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain and are activated in a variety of normal neurophysiologic processes...
, and GluR4
GRIA4
Glutamate receptor 4 is a protein that in humans is encoded by the GRIA4 gene.-Interactions:GRIA4 has been shown to interact with CACNG2, GRIP1, PICK1 and PRKCG.-RNA editing:...
, alternatively called GluRA-D2 , which combine to form tetramers. Most AMPARs are heterotetrameric, consisting of symmetric 'dimer of dimers' of GluR2 and either GluR1, GluR3 or GluR4. Dimerization starts in 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...
with the interaction of n-terminal LIVBP domains, then "zips up" through the ligand-binding domain into the transmembrane ion pore.
The conformation of the subunit protein in the plasma membrane caused controversy for some time. While the amino acid sequence of the subunit indicated that there seemed to be four transmembrane domains (parts of the protein that pass through the plasma membrane), proteins interacting with the subunit indicated that the N-terminus seemed to be extracellular, while the C-terminus seemed to be intracellular. However, if each of the four transmembrane domains went all the way through the plasma membrane, then the two termini would have to be on the same side of the membrane. It was eventually discovered that the second transmembrane domain is not in fact trans
Trans
Trans is a Latin noun or prefix, meaning "across", "beyond" or "on the opposite side".Trans may refer to:- Science and technology :* Cis-trans isomerism, in chemistry, a form of stereoisomerism...
at all, but kinks back on itself within the membrane and returns to the intracellular side (see schematic diagram). When the four subunits of the tetramer come together, this second membranous domain forms the ion-permeable pore of the receptor.
AMPAR subunits differ most in their c-terminal sequence, which determines their interactions with scaffolding proteins. All AMPARs contain PDZ-binding domains, but which PDZ domain
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals...
they bind to differs. For example, GluR1 binds to SAP97 through SAP97's class I PDZ domain, while GluR2 binds to PICK1
PICK1
PRKCA-binding protein is a protein that in humans is encoded by the PICK1 gene.-Interactions:PICK1 has been shown to interact with HER2/neu, ACCN2, Metabotropic glutamate receptor 7, BNC1, Metabotropic glutamate receptor 3, GRIA4, Dopamine transporter, GRIK1, GRIK2, GRIK3, GRIA2 and GRIA3.-Further...
and GRIP/ABP. Of note, AMPARs cannot directly bind to the common synaptic protein PSD-95 due to incompatible PDZ domains.
Phosphorylation
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of AMPARs can regulate channel localization, conductance, and open probability. GluR1 has four known phosphorylation sites at serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
818 (S818), S831, threonine
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
840, and S845 (other subunits have similar phosphorylation sites, but GluR1 has been the most extensively studied). S818 is phosphorylated by 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...
, and is necessary for long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
(LTP; for GluR1's role in LTP, see below). S831 is phosphorylated by CaMKII and PKC during LTP, which helps deliver GluR1-containing AMPAR to the 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...
, and increases their single channel conductance. The T840 site was more recently discovered, and has been implicated in LTD. Finally, S845 is phosphorylated by PKA which regulates its open probability.
Ion Channel Function
Each AMPAR has four sites to which an agonistAgonist
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...
(such as glutamate) can bind, one for each subunit. The binding site is believed to be formed by the N-tail, and the extracellular loop between transmembrane domains three and four. When an agonist binds, these two loops move towards each other, opening the pore. The channel opens when two sites are occupied, and increases its current as more binding sites are occupied. Once open, the channel may undergo rapid desensitization, stopping the current. The mechanism of desensitization is believed to be due to a small change in angle of one of the parts of the binding site, closing the pore. AMPARs open and close quickly, and are thus responsible for most of the fast excitatory synaptic transmission in the central nervous system. On the other hand, norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
appears to inhibit glutamatergic excitatory postsynaptic potential
Excitatory postsynaptic potential
In neuroscience, an excitatory postsynaptic potential is a temporary depolarization of postsynaptic membrane potential caused by the flow of positively charged ions into the postsynaptic cell as a result of opening of ligand-sensitive channels...
s (EPSPs) in the central nervous system by the activation of alpha-1 adrenergic receptor
Alpha-1 adrenergic receptor
The alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
s.
The AMPAR's permeability to calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
and other cations, such as sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
and potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
, is governed by the GluR2 subunit. If an AMPAR lacks a GluR2 subunit, then it will be permeable to sodium, potassium, and calcium. The presence of a GluR2 subunit will almost always render the channel impermeable to calcium. This is determined by post-transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
al modification - RNA editing
RNA editing
The term RNA editing describes those molecular processes in which the information content in an RNA molecule is altered through a chemical change in the base makeup. To date, such changes have been observed in tRNA, rRNA, mRNA and microRNA molecules of eukaryotes but not prokaryotes...
- of the Q
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
/R
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
editing site of the GluR2 mRNA. Here, A→I editing alters the uncharged 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...
glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
(Q), to the positively-charged arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
(R) in the receptor's ion channel. The positively-charged amino acid at the critical point makes it energetically unfavourable for calcium to enter the cell through the pore. Almost all of the GluR2 subunits in CNS are edited to the GluR2(R) form. This means that the principal ions gated by AMPARs are sodium and potassium, distinguishing AMPARs from NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s (the other main ionotropic glutamate receptors in the brain), which also permit calcium influx. Both AMPA and NMDA receptors, however have an equilibrium potential near 0 mV. The prevention of calcium entry into the cell on activation of GluR2-containing AMPARs is proposed to guard against 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...
.
The subunit composition of the AMPAR is also important for the way this receptor is modulated. If an AMPAR lacks GluR2 subunits, then it is susceptible to being blocked in a voltage-dependent manner by a class of molecules called polyamine
Polyamine
A polyamine is an organic compound having two or more primary amino groups .This class of compounds includes several synthetic substances that are important feedstocks for the chemical industry, such as ethylene diamine , 1,3-diaminopropane , and hexamethylenediamine...
s. Thus, when the neuron is at a depolarized
Depolarization
In biology, depolarization is a change in a cell's membrane potential, making it more positive, or less negative. In neurons and some other cells, a large enough depolarization may result in an action potential...
membrane potential, polyamines will block the AMPAR channel more strongly, preventing the flux of potassium ions through the channel pore. GluR2-lacking AMPARs are, thus, said to have an inwardly rectifying I/V curve, which means that they pass less outward current than inward current.
Alongside RNA editing
RNA editing
The term RNA editing describes those molecular processes in which the information content in an RNA molecule is altered through a chemical change in the base makeup. To date, such changes have been observed in tRNA, rRNA, mRNA and microRNA molecules of eukaryotes but not prokaryotes...
, alternative splicing
Alternative splicing
Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing...
allows a range of functional AMPA receptor subunits beyond what is encoded in the genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....
. In other words, although one gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(GRIA1-4) is encoded for each subunit (GluR1-4), splicing after transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
from DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
allows some exons to be translated interchangeably, leading to several functionally different subunits from each gene.
The flip/flop sequence is one such interchangeable exon. A 38-amino acid sequence found prior to (i.e., towards the C-terminus of) the 4th membranous domain in all four AMPAR subunits, it determines the speed of desensitisation of the receptor and also the speed at which the receptor is resensitised and the rate of channel closing. The flip form is present in prenatal AMPA receptors, and gives a sustained current in response to glutamate activation.
Synaptic Plasticity
AMPA receptors (AMPAR) are both glutamate receptorGlutamate 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...
s and cation channels
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...
that are integral to plasticity
Neuroplasticity
Neuroplasticity is a non-specific neuroscience term referring to the ability of the brain and nervous system in all species to change structurally and functionally as a result of input from the environment. Plasticity occurs on a variety of levels, ranging from cellular changes involved in...
and synaptic transmission at many postsynaptic membranes. One of the most widely and thoroughly investigated forms of plasticity in the nervous system is known as long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
, or LTP. There are two necessary components of LTP: presynaptic glutamate release and postsynaptic depolarization. Therefore, LTP can be induced experimentally in a paired electrophysiological recording
Electrophysiology
Electrophysiology is the study of the electrical properties of biological cells and tissues. It involves measurements of voltage change or electric current on a wide variety of scales from single ion channel proteins to whole organs like the heart...
when a presynaptic cell is stimulated to release glutamate on a postsynaptic cell that is depolarized. The typical LTP induction protocol involves a “tetanus” stimulation, which is a 100 Hz stimulation for 1 second. When one applies this protocol to a pair of cells, one will see a sustained increase of the amplitude of the EPSP following tetanus. This response is very intriguing because it is thought to be the physiological correlate for learning and memory in the cell. In fact, it was recently shown that, following a single paired-avoidance paradigm in mice, LTP could be recorded in some hippocampal
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...
synapses in vivo.
The molecular basis for LTP has been extensively studied, and AMPARs have been shown to play an integral role in the process.
Both GluR1 and GluR2 play an important role in synaptic plasticity. It is now known that the underlying physiological correlate for the increase in EPSP size is a postsynaptic upregulation of AMPARs at the membrane, which is accomplished through the interactions of AMPARs with many cellular proteins.
The simplest explanation for LTP is as follows (see the long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
article for a much more detailed account). Glutamate binds to postsynaptic AMPARs and another glutamate receptor, the NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
(NMDAR). Ligand binding causes the AMPARs to open, and Na+ flows into the postsynaptic cell, resulting in a depolarization. NMDARs, on the other hand, do not open directly because their pores are occluded at resting membrane potential by Mg2+ ions. NMDARs can open only when a depolarization from the AMPAR activation leads to repulsion of the Mg2+ cation out into the extracellular space, allowing the pore to pass current. Unlike AMPARs, however, NMDARs are permeable to both Na+ and Ca2+. The Ca2+ that enters the cell triggers the upregulation of AMPARs to the membrane, which results in a long-lasting increase in EPSP size underlying LTP. The calcium entry also phosphorylates CaMKII, which phosphorylates AMPARs, increasing their single-channel conductance.
AMPA Receptor Trafficking
Molecular and Signaling Response to LTP-Inducing Stimuli
The mechanism for LTP has long been a topic of debate, but, recently, mechanisms have come to some consensus. AMPARs play a key role in this process, as one of the key indicators of LTP induction is the increase in the ratio of AMPAR to NMDARs following high-frequency stimulation. The idea is that AMPARs are trafficked from the dendrite into the synapse and incorporated through some series of signaling cascades.AMPARs are initially regulated at the transcriptional level at their 5’ promoter regions. There is significant evidence pointing towards the transcriptional control of AMPA receptors in longer-term memory through cAMP response element-binding protein (CREB
CREB
CREB is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements , thereby increasing or decreasing the transcription of the downstream genes....
) and Mitogen-activated protein kinases (MAPK). Messages are translated on the rough 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...
(rough ER) and modified there. Subunit compositions are determined at the time of modification at the rough ER. After post-ER processing in the golgi apparatus, AMPARs are released into the perisynaptic membrane as a reserve waiting for the LTP process to be initiated.
The first key step in the process following glutamate binding to NMDARs is the influx of calcium through the NMDAR receptors and the resultant activation of Ca2+/calmodulin-dependent protein kinase
Ca2+/calmodulin-dependent protein kinase
/calmodulin-dependent protein kinases II or CaM kinases II are serine/threonine-specific protein kinases that are regulated by the /calmodulin complex...
(CaMKII). Blocking either this influx or the activation of CaMKII prevents LTP, showing that these are necessary mechanisms for LTP. In addition, profusion of CaMKII into a synapse causes LTP, showing that it is a causal and sufficient mechanism.
CaMKII has multiple modes of activation to cause the incorporation of AMPA receptors into the perisynaptic membrane. The first is direct phosphorylation of synaptic-associated protein 97(SAP97). First, SAP-97 and Myosin-VI, a motor protein, are bound as a complex to the C-terminus of AMPARs. Following phosphorylation by CaMKII, the complex moves into the perisynaptic membrane. The second mode of activation is through the MAPK pathway. CaMKII activates the Ras proteins, which go on to activate p42/44 MAPK, which drives AMPAR insertion directly into the perisynaptic membrane.
AMPA Receptor Trafficking to the PSD in Response to LTP
Once AMPA receptors are transported to the perisynaptic region through PKA or SAP97 phosphorylation, receptors are then trafficked to the postsynaptic densityPostsynaptic density
The postsynaptic density is a protein dense specialization attached to the postsynaptic membrane. PSDs were originally identified by electron microscopy as an electron-dense region at the membrane of a postsynaptic neuron...
(PSD). However, this process of trafficking to the PSD still remains controversial. One possibility is that, during LTP, there is lateral movement of AMPA receptors from perisynpatic sites directly to the PSD. Another possibility is that exocytosis
Exocytosis
Exocytosis , also known as 'The peni-cytosis', is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane...
of intracellular vesicles is responsible for AMPA trafficking to the PSD directly. Recent evidence suggests that both of these processes are happening after an LTP stimulus; however, only the lateral movement of AMPA receptors from the perisynaptic region enhances the number of AMPA receptors at the PSD. The exact mechanism responsible for lateral movement of AMP receptors to the PSD remains to be discovered; however, research has discovered several essential proteins for AMPA receptor trafficking. For example, overexpression of SAP97 leads to increased AMPA receptor trafficking to synapses. In addition to influencing synaptic localization, SAP97 has also been found to influence AMPA receptor conductance in response to glutamate. Myosin
Myosin
Myosins comprise a family of ATP-dependent motor proteins and are best known for their role in muscle contraction and their involvement in a wide range of other eukaryotic motility processes. They are responsible for actin-based motility. The term was originally used to describe a group of similar...
proteins are calcium sensitive motor proteins that have also been found to be essential for AMPA receptor trafficking. Disruption of myosin Vb interaction with Rab11 and Rab11-FIP2 blocks spine growth and AMPA receptor trafficking. Therefore, it is possible that myosin may drive the lateral movement of AMPA receptors in the perisynpatic region to the PSD. Transmembrane AMPA regulatory proteins (TARPs) are a family proteins that associate with AMPA receptors and control their trafficking and conductance. CACNG2
CACNG2
Calcium channel, voltage-dependent, gamma subunit 2, also known as CACNG2 or stargazin is a protein that in humans is encoded by the CACNG2 gene.-Function:...
(Stargazin) is one such protein and is found to bind AMPA receptors in the perisynpatic and postsynaptic regions. The role of stargazin in trafficking between the perisynpatic and postsynaptic regions remains unclear; however, stargazin is essential for immobilizing AMPA receptors in the PSD by interacting with PSD-95. PSD-95 stabilizes AMPA receptors to the synapse and disruption of the stargazin-PSD-95 interaction suppressed synaptic transmission.
Constitutive Trafficking and Changes in Subunit Composition
AMPA receptors are continuously being trafficked (endocytosed, recycled, and reinserted) into and out of the plasma membrane. Recycling endosomes within the dendritic spineDendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...
contain pools of AMPA receptors for such synaptic reinsertion. Two distinct pathways exist for the trafficking of AMPA receptors: a regulated pathway and a constitutive pathway.
In the regulated pathway, GluR1-containing AMPA receptors are trafficked to the synapse in an activity-dependent manner, stimulated by NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
activation. Under basal conditions, the regulated pathway is essentially inactive, being transiently activated only upon the induction of long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
. This pathway is responsible for synaptic strengthening and the initial formation of new memories.
In the constitutive pathway, GluR1-lacking AMPA receptors, usually GluR2-GluR3 heteromeric receptors, replace the GluR1-containing receptors in a one-for-one, activity-independent manner, preserving the total number of AMPA receptors in the synapse. This pathway is responsible for the maintenance of new memories, sustaining the transient changes resulting from the regulated pathway. Under basal conditions, this pathway is routinely active, as it is necessary also for the replacement of damaged receptors.
The GluR1 and GluR4 subunits consist of a long carboxy (C)-tail, whereas the GluR2 and GluR3 subunits consist of a short carboxy-tail. The two pathways are governed by interactions between the C termini of the AMPA receptor subunits and synaptic compounds and proteins. Long C-tails prevent GluR1/4 receptors from being inserted directly into the postsynaptic density zone (PSDZ) in the absence of activity, whereas the short C-tails of GluR2/3 receptors allow them to be inserted directly into the PSDZ. The GluR2 C terminus interacts with and binds to N-ethylmaleimide sensitive fusion protein
N-ethylmaleimide sensitive fusion protein
N-ethylmaleimide-sensitive factor, also known as NSF or N-ethylmaleimide sensitive fusion proteins, is an enzyme which in humans is encoded by the NSF gene.- Function :...
, which allows for the rapid insertion of GluR2-containing AMPA receptors at the synapse. In addition, GluR2/3 subunits are more stably tethered to the synapse than GluR1 subunits.
LTD-induced Endocytosis of AMPA Receptors
Long-term depressionLong-term depression
Long-term depression , in neurophysiology, is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer. LTD occurs in many areas of the CNS with varying mechanisms depending upon brain region and developmental progress...
enacts mechanisms to decrease AMPA receptor density in selected dendritic spines, dependent on clathrin
Clathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice...
and calcineurin
Calcineurin
Calcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and calcium-dependent serine-threonine phosphatase, and formerly known as protein phosphatase 2B . It activates the T cells of the immune system and can be blocked by drugs...
and distinct from that of constitutive AMPAR trafficking. The starting signal for AMPAR endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
is an NMDAR-dependent calcium influx from low-frequency stimulation, which in turn activates protein phosphatases PP1 and calcineurin. However, AMPAR endocytosis has also been activated by voltage-dependent calcium channels, agonism of AMPA receptors, and administration of insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, suggesting general calcium influx as the cause of AMPAR endocytosis. Blockage of PP1 did not prevent AMPAR endocytosis, but antagonist application to calcineurin led to significant inhibition of this process.
Calcineurin interacts with an endocytotic complex at the postsynaptic zone, explaining its effects on LTD. The complex, consisting of a clathrin-coated pit underneath a section of AMPAR-containing plasma membrane and interacting proteins, is the direct mechanism for reduction of AMPARs, in particular GluR2/GluR3 subunit-containing receptors, in the synapse. Interactions from calcineurin activate dynamin
Dynamin
Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamins are principally involved in the scission of newly formed vesicles from the membrane of one cellular compartment and their targeting to, and fusion with, another compartment, both at the cell surface as well as at the...
GTPase activity, allowing the clathrin pit to excise itself from the cell membrane and become a cytoplasmic vesicle. Once the clathrin coat detaches, other proteins can interact directly with the AMPARs using PDZ
PDZ domain
The PDZ domain is a common structural domain of 80-90 amino-acids found in the signaling proteins of bacteria, yeast, plants, viruses and animals...
carboxyl tail domains; for example, glutamate receptor-interacting protein 1 (GRIP1) has been implicated in intracellular sequestration of AMPARs. Intracellular AMPARs are subsequently sorted for degradation by lysosomes or recycling to the cell membrane. For the latter, PICK1
PICK1
PRKCA-binding protein is a protein that in humans is encoded by the PICK1 gene.-Interactions:PICK1 has been shown to interact with HER2/neu, ACCN2, Metabotropic glutamate receptor 7, BNC1, Metabotropic glutamate receptor 3, GRIA4, Dopamine transporter, GRIK1, GRIK2, GRIK3, GRIA2 and GRIA3.-Further...
and PKC can displace GRIP1 to return AMPARs to the surface, reversing the effects of endocytosis and LTD when appropriate. Nevertheless, the highlighted calcium-dependent, dynamin-mediated mechanism above has been implicated as a key component of LTD and as such may have applications to further behavioral research.
Agonists
- 5-Fluorowillardiine5-Fluorowillardiine5-Fluorowillardiine is a selective agonist for the AMPA receptor, with only limited effects at the kainate receptor. It is an excitotoxic neurotoxin when used in vivo and so is rarely used in intact animals, but it is widely used to selectively stimulate AMPA receptors in vitro.5-Fluorowillardiine...
- AMPAAMPAAMPA is a compound that is a specific agonist for the AMPA receptor, where it mimics the effects of the neurotransmitter glutamate....
- Domoic acidDomoic acidDomoic acid , the neurotoxin that causes amnesic shellfish poisoning , also known as zombie acid, is a kainic acid analog, heterocyclic amino acid associated with certain harmful algal blooms.-Occurrence:...
- Quisqualic acidQuisqualic acidQuisqualic acid is an agonist for both AMPA receptors and group I metabotropic glutamate receptors. It causes excitotoxicity and is used in neuroscience to selectively destroy neurons in the brain or spinal cord...
- PerampanelPerampanelPerampanel is a drug developed by Eisai Co., which acts as a selective antagonist for the AMPA subtype of ionotropic glutamate receptors. It is being researched for several possible clinical applications including the treatment of Parkinson's disease....
Positive allosteric modulators
- AniracetamAniracetamAniracetam is an ampakine and nootropic of the racetam chemical class purported to be considerably more potent than piracetam. It is lipid-soluble and has possible cognition-enhancing effects. It has been tested in animals extensively, Alzheimer's patients, and temporarily-impaired healthy subjects...
- CyclothiazideCyclothiazideCyclothiazide is a benzothiadiazide diuretic and antihypertensive that was originally introduced in the United States in 1963 by Eli Lilly and was subsequently also marketed in Europe and Japan...
- CX-516CX-516CX-516 is an ampakine and nootropic that acts as an AMPA receptor positive allosteric modulator and is being developed by a collaboration of Cortex and Shire and Servier...
- CX-546
- CX-614
- derivative 11r
- CX-691
- CX-717
- IDRA-21IDRA-21IDRA-21 is an ampakine drug derived from aniracetam. IDRA-21 is a chiral molecule, with -IDRA-21 being the active form.IDRA-21 shows nootropic effects in animal studies, significantly improving learning and memory...
- LY-392,098
- LY-404,187LY-404,187LY-404,187 is an ampakine developed by Eli Lilly and Company. It is a member of the biarylpropylsulfonamide class of ampakines....
- LY-451,395
- LY-451,646
- LY-503,430LY-503,430LY-503,430 is an ampakine drug developed by Eli Lilly.LY-503,430 produces both nootropic and neuroprotective effects, reducing brain damage caused by 6-hydroxydopamine or MPTP and also increasing levels of the neurotrophic factor BDNF in the brain, particularly in the substantia nigra, hippocampus...
- OxiracetamOxiracetamOxiracetam is a nootropic drug of the racetam family.Several animal studies suggest that the substance is safe even when high doses are consumed for a long period of time...
- PEPAPEPA (drug)PEPA is an ampakine drug which acts as an allosteric potentiator of AMPA receptor desensitisation, which is up to 100x more potent than aniracetam in vitro. It produces memory-enhancing effects in rats when administered intravenously.-References:...
- PiracetamPiracetamPiracetam is a nootropic drug. Piracetam's chemical name is 2-oxo-1-pyrrolidine acetamide; it shares the same 2-oxo-pyrrolidone base structure with 2-oxo-pyrrolidine carboxylic acid . Piracetam is a cyclic derivative of GABA. It is one of the group of racetams...
- PramiracetamPramiracetamPramiracetam is a nootropic dietary supplement derived from piracetam, and is more potent . It belongs to the racetam family of nootropics....
- SunifiramSunifiramSunifiram is an ampakine drug which acts as a positive allosteric modulator of AMPA receptors, and has nootropic effects in animal studies with significantly higher potency than piracetam. A number of related compounds are known, the best known being unifiram .-References:...
- UnifiramUnifiramUnifiram is an ampakine drug which acts as a positive allosteric modulator of AMPA receptors, and has nootropic effects in animal studies with up to a thousand times higher potency than piracetam. A number of related compounds are known, the best known being sunifiram...
Antagonists
- CNQXCNQXCNQX is a competitive AMPA/kainate receptor antagonist. Its chemical formula is C9H4N4O4.-External links:**...
- Kynurenic acidKynurenic acidKynurenic acid is a product of the normal metabolism of amino acid L-tryptophan. It has been shown that kynurenic acid possesses neuroactive activity. It acts as an antiexcitotoxic and anticonvulsant, most likely through acting as an antagonist at excitatory amino acid receptors...
- endogenous ligand - NBQXNBQXNBQX is an AMPA receptor antagonist.NBQX blocks AMPA receptors in micromolar concentrations and also blocks kainate receptors. In experiments, it is used to counter glutamate excitotoxicity. NBQX was found to have anticonvulsant activity in rodent seizure models...
- Selective for AMPA receptor over Kainate receptorKainate receptorKainate receptors, or KARs, are non-NMDA ionotropic receptors which respond to the neurotransmitter glutamate. They were first identified as a distinct receptor type through their selective activation by the agonist kainate, a drug first isolated from red algae Digenea simplex. KARs are less well... - TezampanelTezampanelTezampanel is a drug originally developed by Eli Lilly which acts as an antagonist at the AMPA and kainate families of ionotropic glutamate receptors, with selectivity for the GluR5 subtype of the kainate receptor. It has neuroprotective and anticonvulsant effects...
- L-Theanine
Negative allosteric modulators
- GYKI-52,466
- GYKI-53,655
- PerampanelPerampanelPerampanel is a drug developed by Eisai Co., which acts as a selective antagonist for the AMPA subtype of ionotropic glutamate receptors. It is being researched for several possible clinical applications including the treatment of Parkinson's disease....
- TalampanelTalampanelTalampanel is a drug which is being investigated for the treatment of epilepsy, malignant gliomas and amyotrophic lateral sclerosis ..As of May 2010, results from the trial for ALS have been found negative....