AMPA receptor

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The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB 3KG2


The AMPA receptor in animated 3D gif format, PDB 3KG2


AMPA


Glutamic acid
The -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, orquisqualate receptor) is a non-NMDA-
type ionotropic transmembrane receptor for glutamate that mediates fastsynaptic transmission in the central nervous system (CNS). Its name is derived from its ability to be
activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring
agonist quisqualate and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of
Pharmacy in Copenhagen.
[1]
AMPARs are found in many parts of the brain and are the most commonly found receptor in the nervous system. The AMPA receptor GluA2
(GluR2) tetramer was the first and currently only glutamate receptor ion channel to be crystallized.
Contents
[hide]
1 Structure and function
o 1.1 Subunit composition
o 1.2 Ion channel function
2 Synaptic plasticity
o 2.1 AMPA receptor trafficking
2.1.1 Molecular and signaling response to LTP-inducing stimuli
2.1.2 AMPA receptor trafficking to the PSD in response to LTP
2.1.3 Constitutive trafficking and changes in subunit composition
2.1.4 LTD-induced endocytosis of AMPA receptors
2.1.5 Molecular target for epilepsy therapy
3 Ligands
o 3.1 Agonists
o 3.2 Positive allosteric modulators
o 3.3 Antagonists
o 3.4 Negative allosteric modulators
4 See also
5 References
6 External links
Structure and function[edit]
Subunit composition[edit]
AMPARs are composed of four types of subunits, designated as GluR1 (GRIA1), GluR2 (GRIA2), GluR3 (GRIA3), and GluR4, alternatively called GluRA-D2 (GRIA4), which
combine to form tetramers.
[2][3][4]
Most AMPARs are heterotetrameric, consisting of symmetric 'dimer of dimers' of GluR2 and either GluR1, GluR3 or GluR4.
[5][6]
Dimerization
starts in the Endoplasmic reticulum with the interaction of n-terminal LIVBP domains, then "zips up" through the ligand-binding domain into the transmembrane ion pore.
[6]

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 wit h 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 wentall 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 at all, but kinks back on itself within the membrane and returns to the intracellular side.
[7]
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 they bind to differs. For example, GluR1 binds toSAP97 through SAP97's class I PDZ domain,
[8]
while GluR2 binds to PICK1
[9]
and GRIP/ABP. Of note,
AMPARs cannot directly bind to the common synaptic protein PSD-95 due to incompatible PDZ domains, although it does interact with PSD-95 via stargazin (the prototypical
member of the TARP family of AMPAR auxiliary subunits).
[10]

Phosphorylation of AMPARs can regulate channel localization, conductance, and open probability. GluR1 has four known phosphorylation sites at serine 818 (S818),
S831, threonine 840, and S845 (other subunits have similar phosphorylation sites, but GluR1 has been the most extensively studied). S818 i s phosphorylated by protein
kinase C, and is necessary for long-term potentiation (LTP; for GluR1's role in LTP, see below).
[11]
S831 is phosphorylated by CaMKII and PKC during LTP, which helps deliver
GluR1-containing AMPAR to the synapse,
[12]
and increases their single channel conductance.
[13]
The T840 site was more recently discovered, and has been implicated in
LTD.
[14]
Finally, S845 is phosphorylated by PKA which regulates its open probability.
[15]

Ion channel function[edit]
Each AMPAR has four sites to which an agonist (such as glutamate) can bind, one for each subunit.
[5]
The binding site is believed to be formed by the N-tail, and the
extracellular loop between transmembrane domains three and four.
[16]
When an agonist binds, these two loops move towards each other, opening the pore. The channel
opens when two sites are occupied,
[17]
and increases its current as more binding sites are occupied.
[18]
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.
[19]
AMPARs open and
close quickly, and are thus responsible for most of the fast excitatorysynaptic transmission in the central nervous system.
[17]
On the other hand, norepinephrine appears to
inhibit glutamatergic excitatory postsynaptic potentials (EPSPs) in the central nervous system by the activation of alpha-1 adrenergic receptors.
[20]

The AMPAR's permeability to calcium and other cations, such as sodium and potassium, 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-
transcriptional modification - RNA editing - of the Q/R editing site of the GluR2 mRNA. Here, AI editing alters the uncharged amino acid glutamine (Q), to the positively-
charged arginine (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 receptors (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.
[21]

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 polyamines. Thus, when the neuron is at a depolarized 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, alternative splicing allows a range of functional AMPA receptor subunits beyond what is encoded in the genome. In other words, although
one gene (GRIA1-4) is encoded for each subunit (GluR1-4), splicing after transcription from DNA 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., before the N-terminus of) the 4th membranous domain in all four
AMPAR subunits, it determines the speed of desensitisation
[22]
of the receptor and also the speed at which the receptor is resensitised
[23]
and the rate of channel
closing.
[24]
The flip form is present in prenatal AMPA receptors, and gives a sustained current in response to glutamate activation.
[25]

Synaptic plasticity[edit]
AMPA receptors (AMPAR) are both glutamate receptors and cation channels that are integral to plasticity 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, 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 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 synapses in vivo.
[26]

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 article for a much more detailed account). Glutamate binds to postsynaptic AMPARs and another
glutamate receptor, the NMDA receptor (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 Mg
2+
ions. NMDARs can open only when a
depolarization from the AMPAR activation leads to repulsion of the Mg
2+
cation out into the extracellular space, allowing the pore to pass current. Unlike AMPARs, however,
NMDARs are permeable to both Na
+
and Ca
2+
. The Ca
2+
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[edit]


Regulation of AMPAR trafficking to the postsynaptic density in response to LTP-inducing stimuli
Molecular and signaling response to LTP-inducing stimuli[edit]
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 point ing towards the transcriptional control of AMPA
receptors in longer-term memory through cAMP response element-binding protein (CREB) andMitogen-activated protein kinases (MAPK).Perkinton MS, Sihra TS, Williams RJ
(July 1999). "Ca(2+)-permeable AMPA receptors induce phosphorylation of cAMP response element-binding protein through a phosphatidylinositol 3-kinase-dependent
stimulation of the mitogen-activated protein kinase signaling cascade in neurons". J. Neurosci. 19 (14): 586174. PMID 10407026. Messages are translated on the
rough endoplasmic reticulum (rough ER) and modified there. Subunit compositions are determined at the time of modification at the rough ER.
[9]
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 NMDA receptors and the resultant activation of [[Ca
2+
/calmodulin-
dependent protein kinase]] (CaMKII).
[27]
Blocking either this influx or the activation of CaMKII prevents LTP, showing that these are necessary mechanisms for LTP.
[28]
In
addition, profusion of CaMKII into a synapse causes LTP, showing that it is a causal and sufficient mechanism.
[29]

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).
[30]
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.
[31]
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.
[32]

AMPA receptor trafficking to the PSD in response to LTP[edit]
Once AMPA receptors are transported to the perisynaptic region through PKA or SAP97 phosphorylation, receptors are then trafficked to the postsynaptic density (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.
[33]
Another possibility is that exocytosis of intracellular vesicles is responsible for AMPA trafficking to the PSD directly.
[34]
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.
[35]
The exact mechanism responsible for lateral movement of AMPA 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.
[36]
In
addition to influencing synaptic localization, SAP97 has also been found to influence AMPA receptor conductance in response to glutamate.
[37]
Myosin 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.
[38]
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.
[39]
CACNG2 (Stargazin) is one such protein and is found to bind AMPA receptors in the perisynpatic and postsynaptic regions.
[40]
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.
[41]
PSD-95 stabilizes AMPA receptors to the synapse and disruption of the stargazin-PSD-95 interaction suppressed synaptic transmission.
[42]

Constitutive trafficking and changes in subunit composition[edit]
AMPA receptors are continuously being trafficked (endocytosed, recycled, and reinserted) into and out of the plasma membrane. Recycling endosomes within the dendritic
spine contain pools of AMPA receptors for such synaptic reinsertion.
[43]
Two distinct pathways exist for the trafficking of AMPA receptors: a regulated pathway and a
constitutive pathway.
[44][45]

In the regulated pathway, GluR1-containing AMPA receptors are trafficked to the synapse in an activity-dependent manner, stimulated by NMDA receptor activation.
[12]
Under
basal conditions, the regulated pathway is essentially inactive, being transiently activated only upon the induction of long-term potentiation.
[43][44]
This pathway is responsible
for synaptic strengthening and the initial formation of new memories.
[46]

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,
[47][48]
preserving the total number of AMPA receptors in the synapse.
[43][44]
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 i s 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.
[33][49]
The
GluR2 C terminus interacts with and binds to N-ethylmaleimide sensitive fusion protein,
[50][51][52]
which allows for the rapid insertion of GluR2-containing AMPA receptors at the
synapse.
[53]
In addition, GluR2/3 subunits are more stably tethered to the synapse than GluR1 subunits.
[54][55][56]

LTD-induced endocytosis of AMPA receptors[edit]


LTD-induced endocytosis of AMPA receptors
Long-term depression enacts mechanisms to decrease AMPA receptor density in selected dendritic spines, dependent onclathrin and calcineurin and distinct from that of
constitutive AMPAR trafficking. The starting signal for AMPAR endocytosisis an NMDAR-dependent calcium influx from low-frequency stimulation, which in turn activates
protein phosphatases PP1and calcineurin. However, AMPAR endocytosis has also been activated by voltage-dependent calcium channels, agonism of AMPA receptors, and
administration of insulin, suggesting general calcium influx as the cause of AMPAR endocytosis.
[57]
Blockage of PP1 did not prevent AMPAR endocytosis, but antagonist
application to calcineurin led to significant inhibition of this process.
[58]

Calcineurin interacts with an endocytotic complex at the postsynaptic zone, explaining its effects on LTD.
[59]
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 GTPase activity, allowing the clathrin pit to excise itself from the cell membrane and become a
cytoplasmic vesicle.
[60]
Once the clathrin coat detaches, other proteins can interact directly with the AMPARs using PDZ carboxyl tail domains; for example, glutamate
receptor-interacting protein 1 (GRIP1) has been implicated in intracellular sequestration of AMPARs.
[61]
Intracellular AMPARs are subsequently sorted for degradation by
lysosomes or recycling to the cell membrane.
[62]
For the latter, PICK1and PKC can displace GRIP1 to return AMPARs to the surface, reversing the effects of endocytosis and
LTD when appropriate.
[63]
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.
[64]

Molecular target for epilepsy therapy[edit]
The noncompetitive AMPA receptor antagonists talampanel and perampanel have been demonstrated to have activity in the treatment of adults with partial
seizures,
[65][66]
indicating that AMPA receptor antagonists represent a potential target for the treatment of epilepsy.
[67]

[68]
Perampanel (trade name: Fycompa) received
Marketing Authorisation Approval by the European Commission for the treatment of partial epilepsy on July 27, 2012. The drug was approved in the United States by the Food
and Drug Administration (FDA) on October 22, 2012. As has been the case for most recently developed AEDs including pregabalin, lacosamide and ezogabine, the FDA
recommended that perampanel be classified by the Drug Enforcement Administration (DEA) as a scheduled drug; it will be made available pending final scheduling
designation.
Ligands[edit]
Agonists[edit]
5-Fluorowillardiine
AMPA
Domoic acid
Quisqualic acid
Positive allosteric modulators[edit]
Aniracetam
Cyclothiazide
CX-516
CX-546
CX-614
derivative 11r
[69]

CX-691
CX-717
IDRA-21
Org 26576
LY-392,098
LY-404,187
LY-451,395
LY-451,646
LY-503,430
[70][71]

Oxiracetam
PEPA
Piracetam
Pramiracetam
Sunifiram
Unifiram
Antagonists[edit]
CNQX
Ethanol
Kynurenic acid - endogenous ligand
NBQX - Selective for AMPA receptor over Kainate receptor
Perampanel
Tezampanel
L-Theanine
Negative allosteric modulators[edit]
GYKI-52,466
GYKI-53,655
Perampanel
Talampanel
See also[edit]
Arc/Arg3.1
References[edit]
1. Jump up^ Honore T, Lauridsen J, Krogsgaard-Larsen P (1982). "The binding of [3H]AMPA, a structural
analogue of glutamic acid, to rat brain membranes". Journal of Neurochemistry 38 (1): 173
178. doi:10.1111/j.1471-4159.1982.tb10868.x. PMID 6125564
2. Jump up^ "Glutamate receptors: Structures and functions. University of Bristol Centre for Synaptic
Plasticity.". Archived from the original on 15 September 2007. Retrieved 2007-09-02.
3. Jump up^ Shi SH, Hayashi Y, Petralia RS, et al. (1999). "Rapid spine delivery and redistribution of
AMPA receptors after synaptic NMDA receptor activation". Science 284 (5421): 1811
6.doi:10.1126/science.284.5421.1811. PMID 10364548.
4. Jump up^ Song I, Huganir RL (2002). "Regulation of AMPA receptors during synaptic plasticity". Trends
Neurosci. 25 (11): 57888. doi:10.1016/S0166-2236(02)02270-1. PMID 12392933.
5. ^ Jump up to:
a

b
Mayer, M. L. (2005). "Glutamate receptor ion channels". Current Opinion in
Neurobiology15 (3): 282288. doi:10.1016/j.conb.2005.05.004. PMID 15919192.
6. ^ Jump up to:
a

b
Greger IH, Ziff EB, Penn AC (August 2007). "Molecular determinants of AMPA receptor
subunit assembly". Trends Neurosci. 30 (8): 40716. doi:10.1016/j.tins.2007.06.005.PMID 17629578.
7. Jump up^ Hollmann M, Maron C, Heinemann S (1994). "N-glycosylation site tagging suggests a three
transmembrane domain topology for the glutamate receptor GluR1". Neuron 13 (6): 1331
43.doi:10.1016/0896-6273(94)90419-7. PMID 7993626.
8. Jump up^ Leonard AS, Davare MA, Horne MC, Garner CC, Hell JW (July 1998). "SAP97 is associated
with the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor GluR1 subunit". J. Biol.
Chem. 273 (31): 1951824. doi:10.1074/jbc.273.31.19518. PMID 9677374.
9. ^ Jump up to:
a

b
Greger IH, Khatri L, Ziff EB (May 2002). "RNA editing at arg607 controls AMPA receptor
exit from the endoplasmic reticulum". Neuron 34 (5): 75972. doi:10.1016/S0896-6273(02)00693-
1. PMID 12062022.
10. Jump up^ Bats C, Groc L, Choquet D. (2007). "The interaction between Stargazin and PSD-95
regulates AMPA receptor surface trafficking.". Neuron 53 (5): 719
34.doi:10.1016/j.neuron.2007.01.030. PMID 17329211.
11. Jump up^ Boehm J, Kang MG, Johnson RC, Esteban J, Huganir RL, Malinow R (July 2006). "Synaptic
incorporation of AMPA receptors during LTP is controlled by a PKC phosphorylation site on
GluR1". Neuron 51 (2): 21325. doi:10.1016/j.neuron.2006.06.013. PMID 16846856.
12. ^ Jump up to:
a

b
Hayashi Y, Shi SH, Esteban JA, Piccini A, Poncer JC, Malinow R (March 2000). "Driving
AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain
interaction". Science 287 (5461): 22627. doi:10.1126/science.287.5461.2262.PMID 10731148.
13. Jump up^ Derkach V, Barria A, Soderling TR (March 1999). "Ca2+/calmodulin-kinase II enhances
channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate
receptors". Proc. Natl. Acad. Sci. U.S.A. 96 (6): 3269
74. doi:10.1073/pnas.96.6.3269.PMC 15931. PMID 10077673.
14. Jump up^ Delgado JY, Coba M, Anderson CN, et al. (November 2007). "NMDA receptor activation
dephosphorylates AMPA receptor glutamate receptor 1 subunits at threonine 840". J. Neurosci. 27 (48):
1321021. doi:10.1523/JNEUROSCI.3056-07.2007. PMC 2851143.PMID 18045915.
15. Jump up^ Banke TG, Bowie D, Lee H, Huganir RL, Schousboe A, Traynelis SF (January
2000). "Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase". J.
Neurosci. 20 (1): 89102. PMID 10627585.
16. Jump up^ Armstrong N, Sun Y, Chen GQ, Gouaux E (October 1998). "Structure of a glutamate-receptor
ligand-binding core in complex with kainate". Nature 395 (6705): 913
7. doi:10.1038/27692.PMID 9804426.
17. ^ Jump up to:
a

b
Platt SR (2007). "The role of glutamate in central nervous system health and disease--a
review". Vet. J. 173 (2): 27886. doi:10.1016/j.tvjl.2005.11.007. PMID 16376594.
18. Jump up^ Rosenmund C, Stern-Bach Y, Stevens CF (June 1998). "The tetrameric structure of a
glutamate receptor channel". Science 280 (5369): 1596
9.doi:10.1126/science.280.5369.1596. PMID 9616121.
19. Jump up^ Armstrong N, Jasti J, Beich-Frandsen M, Gouaux E (October 2006). "Measurement of
conformational changes accompanying desensitization in an ionotropic glutamate receptor".Cell 127 (1):
8597. doi:10.1016/j.cell.2006.08.037. PMID 17018279.
20. Jump up^ Dinh L, Nguyen T, Salgado H, Atzori M (November 2009). "Norepinephrine homogeneously
inhibits alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate- (AMPAR-) mediated currents in all
layers of the temporal cortex of the rat". Neurochem. Res. 34 (11): 1896906.doi:10.1007/s11064-009-
9966-z. PMID 19357950.
21. Jump up^ Kim DY, Kim SH, Choi HB, Min C, Gwag BJ (2001). "High abundance of GluR1 mRNA and
reduced Q/R editing of GluR2 mRNA in individual NADPH-diaphorase neurons". Mol. Cell.
Neurosci. 17 (6): 102533. doi:10.1006/mcne.2001.0988. PMID 11414791.
22. Jump up^ Mosbacher J, Schoepfer R, Monyer H, Burnashev N, Seeburg PH, Ruppersberg JP (1994).
"A molecular determinant for submillisecond desensitization in glutamate receptors". Science 266(5187):
105962. doi:10.1126/science.7973663. PMID 7973663.
23. Jump up^ Sommer B, Keinnen K, Verdoorn TA, et al. (1990). "Flip and flop: a cell-specific functional
switch in glutamate-operated channels of the CNS". Science 249 (4976): 1580
5.doi:10.1126/science.1699275. PMID 1699275.
24. Jump up^ Pei W, Huang Z, Niu L. (2007). "GluR3 flip and flop: differences in channel opening
kinetics".Biochemistry 46 (7): 202736. doi:10.1021/bi062213s. PMID 17256974.
25. Jump up^ GluR2 glutamate receptor subunit flip and flop isoforms are decreased in the hippocampal
formation in schizophrenia: a reverse transcriptase-polymerase chain reaction (RTPCR) study,
Eastwood et al., Molecular Brain Research Vol44, Iss1, Feb1997, Pg92-98
26. Jump up^ Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006). "Learning induces long-term
potentiation in the hippocampus". Science 313 (5790): 1093
7.doi:10.1126/science.1128134. PMID 16931756.
27. Jump up^ Fukunaga K, Stoppini L, Miyamoto E, Muller D (April 1993). "Long-term potentiation is
associated with an increased activity of Ca2+/calmodulin-dependent protein kinase II". J. Biol.
Chem. 268 (11): 78637. PMID 8385124.
28. Jump up^ Lisman J, Schulman H, Cline H (March 2002). "The molecular basis of CaMKII function in
synaptic and behavioural memory". Nat. Rev. Neurosci. 3 (3): 175
90. doi:10.1038/nrn753.PMID 11994750.
29. Jump up^ Mammen AL, Kameyama K, Roche KW, Huganir RL (December 1997). "Phosphorylation of
the alpha-amino-3-hydroxy-5-methylisoxazole4-propionic acid receptor GluR1 subunit by
calcium/calmodulin-dependent kinase II". J. Biol. Chem. 272 (51): 32528
33.doi:10.1074/jbc.272.51.32528. PMID 9405465.
30. Jump up^ Mauceri D, Cattabeni F, Di Luca M, Gardoni F (May 2004). "Calcium/calmodulin-dependent
protein kinase II phosphorylation drives synapse-associated protein 97 into spines". J. Biol.
Chem. 279 (22): 2381321. doi:10.1074/jbc.M402796200. PMID 15044483.
31. Jump up^ Wu H, Nash JE, Zamorano P, Garner CC (August 2002). "Interaction of SAP97 with minus-
end-directed actin motor myosin VI. Implications for AMPA receptor trafficking". J. Biol. Chem.277 (34):
3092834. doi:10.1074/jbc.M203735200. PMID 12050163.
32. Jump up^ Zhu JJ, Qin Y, Zhao M, Van Aelst L, Malinow R (August 2002). "Ras and Rap control AMPA
receptor trafficking during synaptic plasticity". Cell 110 (4): 44355. doi:10.1016/S0092-8674(02)00897-
8. PMID 12202034.
33. ^ Jump up to:
a

b
Borgdorff AJ, Choquet D (June 2002). "Regulation of AMPA receptor lateral
movements".Nature 417 (6889): 64953. doi:10.1038/nature00780. PMID 12050666.
34. Jump up^ Park M, Penick EC, Edwards JG, Kauer JA, Ehlers MD (September 2004). "Recycling
endosomes supply AMPA receptors for LTP". Science 305 (5692): 1972
5.doi:10.1126/science.1102026. PMID 15448273.
35. Jump up^ Makino H, Malinow R (November 2009). "AMPA receptor incorporation into synapses during
LTP: the role of lateral movement and exocytosis". Neuron 64 (3): 381
90.doi:10.1016/j.neuron.2009.08.035. PMC 2999463. PMID 19914186.
36. Jump up^ Howard MA, Elias GM, Elias LA, Swat W, Nicoll RA (February 2010). "The role of SAP97 in
synaptic glutamate receptor dynamics". Proc. Natl. Acad. Sci. U.S.A. 107 (8): 3805
10.doi:10.1073/pnas.0914422107. PMC 2840522. PMID 20133708.
37. Jump up^ Waites CL, Specht CG, Hrtel K, Leal-Ortiz S, Genoux D, Li D, Drisdel RC, Jeyifous O,
Cheyne JE, Green WN, Montgomery JM, Garner CC (April 2009). "Synaptic SAP97 isoforms regulate
AMPA receptor dynamics and access to presynaptic glutamate". J. Neurosci. 29 (14): 4332
45. doi:10.1523/JNEUROSCI.4431-08.2009. PMC 3230533. PMID 19357261.
38. Jump up^ Wang Z, Edwards JG, Riley N, Provance DW, Karcher R, Li XD, Davison IG, Ikebe M,
Mercer JA, Kauer JA, Ehlers MD (October 2008). "Myosin Vb mobilizes recycling endosomes and AMPA
receptors for postsynaptic plasticity". Cell 135 (3): 535
48. doi:10.1016/j.cell.2008.09.057.PMC 2585749. PMID 18984164.
39. Jump up^ Nicoll RA, Tomita S, Bredt DS (March 2006). "Auxiliary subunits assist AMPA-type glutamate
receptors". Science 311 (5765): 12536. doi:10.1126/science.1123339. PMID 16513974.
40. Jump up^ Tomita S, Chen L, Kawasaki Y, Petralia RS, Wenthold RJ, Nicoll RA, Bredt DS (May
2003)."Functional studies and distribution define a family of transmembrane AMPA receptor regulatory
proteins". J. Cell Biol. 161 (4): 80516. doi:10.1083/jcb.200212116. PMC 2199354.PMID 12771129.
41. Jump up^ Chen L, Chetkovich DM, Petralia RS, Sweeney NT, Kawasaki Y, Wenthold RJ, Bredt DS,
Nicoll RA (2000). "Stargazin regulates synaptic targeting of AMPA receptors by two distinct
mechanisms". Nature 408 (6815): 93643. doi:10.1038/35050030. PMID 11140673.
42. Jump up^ Bats C, Groc L, Choquet D (March 2007). "The interaction between Stargazin and PSD-95
regulates AMPA receptor surface trafficking". Neuron 53 (5): 719
34.doi:10.1016/j.neuron.2007.01.030. PMID 17329211.
43. ^ Jump up to:
a

b

c
Shepherd JD, Huganir RL (2007). "The cell biology of synaptic plasticity: AMPA
receptor trafficking". Annu. Rev. Cell Dev. Biol. 23: 613
43.doi:10.1146/annurev.cellbio.23.090506.123516. PMID 17506699.
44. ^ Jump up to:
a

b

c
Malinow R, Mainen ZF, Hayashi Y (June 2000). "LTP mechanisms: from silence to
four-lane traffic". Curr. Opin. Neurobiol. 10 (3): 3527. doi:10.1016/S0959-4388(00)00099-
4.PMID 10851179.
45. Jump up^ Malenka RC (November 2003). "Synaptic plasticity and AMPA receptor trafficking". Ann. N.
Y. Acad. Sci. 1003: 111. PMID 14684431.
46. Jump up^ Kessels HW, Malinow R (February 2009). "Synaptic AMPA receptor plasticity and
behavior".Neuron 61 (3): 34050. doi:10.1016/j.neuron.2009.01.015. PMC 3917551.PMID 19217372.
47. Jump up^ McCormack SG, Stornetta RL, Zhu JJ (April 2006). "Synaptic AMPA receptor exchange
maintains bidirectional plasticity". Neuron 50 (1): 75
88. doi:10.1016/j.neuron.2006.02.027.PMID 16600857.
48. Jump up^ Zhu JJ, Esteban JA, Hayashi Y, Malinow R (November 2000). "Postnatal synaptic
potentiation: delivery of GluR4-containing AMPA receptors by spontaneous activity". Nat.
Neurosci. 3 (11): 1098106. doi:10.1038/80614. PMID 11036266.
49. Jump up^ Passafaro M, Pich V, Sheng M (September 2001). "Subunit-specific temporal and spatial
patterns of AMPA receptor exocytosis in hippocampal neurons". Nat. Neurosci. 4 (9): 917
26.doi:10.1038/nn0901-917. PMID 11528423.
50. Jump up^ Song I, Kamboj S, Xia J, Dong H, Liao D, Huganir RL (August 1998). "Interaction of the N-
ethylmaleimide-sensitive factor with AMPA receptors". Neuron 21 (2): 393400.doi:10.1016/S0896-
6273(00)80548-6. PMID 9728920.
51. Jump up^ Osten P, Srivastava S, Inman GJ, Vilim FS, Khatri L, Lee LM, States BA, Einheber S, Milner
TA, Hanson PI, Ziff EB (July 1998). "The AMPA receptor GluR2 C terminus can mediate a reversible,
ATP-dependent interaction with NSF and alpha- and beta-SNAPs". Neuron 21 (1): 99
110.doi:10.1016/S0896-6273(00)80518-8. PMID 9697855.
52. Jump up^ Nishimune A, Isaac JT, Molnar E, Noel J, Nash SR, Tagaya M, Collingridge GL, Nakanishi S,
Henley JM (July 1998). "NSF binding to GluR2 regulates synaptic transmission". Neuron 21 (1): 87
97. doi:10.1016/S0896-6273(00)80517-6. PMID 9697854.
53. Jump up^ Beretta F, Sala C, Saglietti L, Hirling H, Sheng M, Passafaro M (April 2005). "NSF interaction
is important for direct insertion of GluR2 at synaptic sites". Mol. Cell. Neurosci. 28 (4): 650
60.doi:10.1016/j.mcn.2004.11.008. PMID 15797712.
54. Jump up^ Cingolani LA, Thalhammer A, Yu LM, Catalano M, Ramos T, Colicos MA, Goda Y (June
2008)."Activity-dependent regulation of synaptic AMPA receptor composition and abundance by beta3
integrins". Neuron 58 (5): 74962. doi:10.1016/j.neuron.2008.04.011. PMC 2446609.PMID 18549786.
55. Jump up^ Saglietti L, Dequidt C, Kamieniarz K, Rousset MC, Valnegri P, Thoumine O, Beretta F, Fagni
L, Choquet D, Sala C, Sheng M, Passafaro M (May 2007). "Extracellular interactions between GluR2
and N-cadherin in spine regulation". Neuron 54 (3): 461
77.doi:10.1016/j.neuron.2007.04.012. PMID 17481398.
56. Jump up^ Silverman JB, Restituito S, Lu W, Lee-Edwards L, Khatri L, Ziff EB (August 2007). "Synaptic
anchorage of AMPA receptors by cadherins through neural plakophilin-related arm protein AMPA
receptor-binding protein complexes". J. Neurosci. 27 (32): 850516.doi:10.1523/JNEUROSCI.1395-
07.2007. PMID 17687028.
57. Jump up^ Carroll RC, Beattie EC, Xia H, Lscher C, Altschuler Y, Nicoll RA, Malenka RC, von Zastrow
M (November 1999). "Dynamin-dependent endocytosis of ionotropic glutamate receptors".Proc. Natl.
Acad. Sci. U.S.A. 96 (24): 141127. doi:10.1073/pnas.96.24.14112.PMC 24199. PMID 10570207.
58. Jump up^ Beattie EC, Carroll RC, Yu X, Morishita W, Yasuda H, von Zastrow M, Malenka RC
(December 2000). "Regulation of AMPA receptor endocytosis by a signaling mechanism shared with
LTD".Nat. Neurosci. 3 (12): 1291300. doi:10.1038/81823. PMID 11100150.
59. Jump up^ Lai MM, Hong JJ, Ruggiero AM, Burnett PE, Slepnev VI, De Camilli P, Snyder SH
(September 1999). "The calcineurin-dynamin 1 complex as a calcium sensor for synaptic vesicle
endocytosis". J. Biol. Chem. 274 (37): 259636. PMID 10473536.
60. Jump up^ Jung N, Haucke V (September 2007). "Clathrin-mediated endocytosis at
synapses". Traffic 8(9): 112936. doi:10.1111/j.1600-0854.2007.00595.x. PMID 17547698.
61. Jump up^ Daw MI, Chittajallu R, Bortolotto ZA, Dev KK, Duprat F, Henley JM, Collingridge GL, Isaac JT
(December 2000). "PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent
regulation of AMPA receptors at hippocampal synapses". Neuron 28 (3): 87386.doi:10.1016/S0896-
6273(00)00160-4. PMID 11163273.
62. Jump up^ Ehlers, MD (2000). "Reinsertion or degradation of AMPA receptors determined by activity-
dependent endocytic sorting". Neuron 28 (2): 51125. doi:10.1016/S0896-6273(00)00129-
X.PMID 11144360.
63. Jump up^ Lu W, Ziff EB (August 2005). "PICK1 interacts with ABP/GRIP to regulate AMPA receptor
trafficking". Neuron 47 (3): 40721. doi:10.1016/j.neuron.2005.07.006. PMID 16055064.
64. Jump up^ Yang, YT (2008). "Probing the role of AMPAR endocytosis and long-term depression in
behavioural sensitization: relevance to treatment of brain disorders, including drug addiction".British
Journal of Pharmacology 153 (S1): S389S395. doi:10.1038/sj.bjp.0707616.
65. Jump up^ Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Perucca E, Tomson T (January 2007).
"Progress report on new antiepileptic drugs: a summary of the Eigth Eilat Conference (EILAT
VIII)". Epilepsy Res. 73 (1): 152. doi:10.1016/j.eplepsyres.2006.10.008. PMID 17158031.
66. Jump up^ French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, Kumar D, Rogawski MA
(August 2012). "Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study
304". Neurology 79 (6): 58996. doi:10.1212/WNL.0b013e3182635735.PMC 3413761. PMID 22843280.
67. Jump up^ Rogawski MA (March 2011). "Revisiting AMPA receptors as an antiepileptic drug
target".Epilepsy Curr 11 (2): 5663. doi:10.5698/1535-7511-11.2.56. PMC 3117497.PMID 21686307.
68. Jump up^ Sakai F, Igarashi H, Suzuki S, Tazaki Y (1989). "Cerebral blood flow and cerebral hematocrit
in patients with cerebral ischemia measured by single-photon emission computed tomography". Acta
Neurol. Scand., Suppl.c 127: 913. doi:10.1111/ane.12099.PMID 2631521.
69. Jump up^ Mueller R, Rachwal S, Tedder ME, Li YX, Zhong S, Hampson A, Ulas J, Varney M, Nielsson
L, Rogers G (July 2011). "Substituted benzoxazinones as potent positive allosteric AMPA receptor
modulators: part II". Bioorg. Med. Chem. Lett. 21 (13): 3927
30.doi:10.1016/j.bmcl.2011.05.024. PMID 21636273.
70. Jump up^ Murray TK, Whalley K, Robinson CS, et al. (2003). "LY503430, a novel alpha-amino-3-
hydroxy-5-methylisoxazole-4-propionic acid receptor potentiator with functional, neuroprotective and
neurotrophic effects in rodent models of Parkinson's disease". J. Pharmacol. Exp. Ther. 306(2): 752
62. doi:10.1124/jpet.103.049445. PMID 12730350.
71. Jump up^ O'Neill MJ, Bleakman D, Zimmerman DM, Nisenbaum ES (2004). "AMPA receptor
potentiators for the treatment of CNS disorders". Curr Drug Targets CNS Neurol Disord 3 (3): 181
94.doi:10.2174/1568007043337508. PMID 15180479.
External links[edit]
AMPA receptors - pharmacology
Drosophila Glutamate receptor IIA - The Interactive Fly
[hide]
V
T
E
Ion channel, cell surface receptor: ligand-gated ion channels

Cys-loop receptors 5-HT/serotonin
5-HT3
A
B
C
D
E

GABA
GABAA
1
2
3
4
5
6
1
2
3
1
2
3




GABAA-
1
2
3

Glycine
1
2
3
4


Nicotinic acetylcholine
monomers: 1
2
3
4
5
6
7
9
10
1
2
3
4


pentamers: (3)2(4)3
(4)2(2)3
(7)5
(1)2(4)3 - Ganglion type
(1)21 - Muscle type

Zinc Zinc-activated


Ionotropic glutamates
Ligand-gatedonly
AMPA (1
2
3
4)
Kainate
1
2
3
4
5

Voltage- andligand-gated
NMDA
1
2A
2B
2C
2D
3A
3B
L1A
L1B

Orphan
GluD
1
2


ATP-gatedchannels Purinergic receptors
P2X
1
2
3
4
5
6
7


B trdu: iter (nrpl/grfl/cytl/horl), csrc (lgic, enzr, gprc, igsr, intg, nrpr/grfr/cytr), itra (adap, gbpr, mapk), calc, lipd; path (hedp, wntp, tgfp+mapp, notp, jakp, fsap, hipp, tlrp)

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Ionotropic receptors
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