AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as
Structure and function
Subunit composition
AMPARs are composed of four types of subunits encoded by different genes, designated as
The conformation of the subunit protein in the
AMPAR subunits differ most in their C-terminal sequence, which determines their interactions with scaffolding proteins. All AMPARs contain PDZ-binding domains, but which
Phosphorylation of AMPARs can regulate channel localization, conductance, and open probability. GluA1 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 is phosphorylated by protein kinase C, and is necessary for long-term potentiation (LTP; for GluA1's role in LTP, see below).[12] S831 is phosphorylated by CaMKII and PKC during LTP, which helps deliver GluA1-containing AMPAR to the synapse,[13] and increases their single channel conductance.[14] The T840 site was more recently discovered, and has been implicated in LTD.[15] Finally, S845 is phosphorylated by PKA which regulates its open probability.[16]
Ion channel function
Each AMPAR has four sites to which an
The subunit composition of the AMPAR is also important for the way this receptor is modulated. If an AMPAR lacks GluA2 subunits, then it is susceptible to being blocked in a voltage-dependent manner by a class of molecules called
Alongside
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 fourth membranous domain in all four AMPAR subunits, it determines the speed of desensitisation[25] of the receptor and also the speed at which the receptor is resensitised[26] and the rate of channel closing.[27] The flip form is present in prenatal AMPA receptors and gives a sustained current in response to glutamate activation.[28]
Synaptic plasticity
AMPA receptors (AMPAR) are both
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,[30] which is accomplished through the interactions of AMPARs with many cellular proteins.
The simplest explanation for LTP is as follows (see the
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 (
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 Ca2+/calmodulin-dependent protein kinase (CaMKII).[32] Blocking either this influx or the activation of CaMKII prevents LTP, showing that these are necessary mechanisms for LTP.[33] In addition, profusion of CaMKII into a synapse causes LTP, showing that it is a causal and sufficient mechanism.[34]
CaMKII has multiple modes of activation to cause the incorporation of AMPA receptors into the perisynaptic membrane. CAMKII enzyme is eventually responsible for the development of the actin cytoskeleton of neuronal cells and, eventually, for the dendrite and axon development (synaptic plasticity).
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
Biophysics of AMPA receptor trafficking
The motion of AMPA receptors on the synaptic membrane are well approximated as a Brownian, which can however be stabilized at the PSD by retention forces. These forces can stabilize receptors transienstly, but allow a constant exchanges with the peri-synaptic domain.[48][49] These forces may results from the PSD local organization, sometimes refer to as phase separation.
Constitutive trafficking and changes in subunit composition
AMPA receptors are continuously being trafficked (endocytosed, recycled, and reinserted) into and out of the
In the regulated pathway, GluA1-containing AMPA receptors are trafficked to the synapse in an activity-dependent manner, stimulated by NMDA receptor activation.[13] Under basal conditions, the regulated pathway is essentially inactive, being transiently activated only upon the induction of long-term potentiation.[50][51] This pathway is responsible for synaptic strengthening and the initial formation of new memories.[53]
In the constitutive pathway, GluA1-lacking AMPA receptors, usually GluR2-GluR3 heteromeric receptors, replace the GluA1-containing receptors in a one-for-one, activity-independent manner,[54][55] preserving the total number of AMPA receptors in the synapse.[50][51] 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 GluA1 and GluA4 subunits consist of a long carboxy (C)-tail, whereas the GluA2 and GluA3 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 GluA2/3 receptors allow them to be inserted directly into the PSDZ.[39][56] The GluA2 C terminus interacts with and binds to N-ethylmaleimide sensitive fusion protein,[57][58][59] which allows for the rapid insertion of GluR2-containing AMPA receptors at the synapse.[60] In addition, GluR2/3 subunits are more stably tethered to the synapse than GluR1 subunits.[61][62][63]
LTD-induced endocytosis of AMPA receptors
Calcineurin interacts with an endocytotic complex at the postsynaptic zone, explaining its effects on LTD.[66] 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.[67] 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.[68] Intracellular AMPARs are subsequently sorted for degradation by lysosomes or recycling to the cell membrane.[69] For the latter, PICK1 and PKC can displace GRIP1 to return AMPARs to the surface, reversing the effects of endocytosis and LTD. when appropriate.[70] 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.[71]
Role in Seizures
AMPA receptors play a key role in the generation and spread of epileptic seizures.
Molecular target for epilepsy therapy
The noncompetitive AMPA receptor antagonists talampanel and perampanel have been demonstrated to have activity in the treatment of adults with partial seizures,[74][75] indicating that AMPA receptor antagonists represent a potential target for the treatment of epilepsy.[76]
Preclinical research suggest that several derivatives of aromatic amino acids with antiglutamatergic properties including AMPA receptor antagonism and inhibition of glutamate release such as 3,5-dibromo-D-tyrosine and 3,5-dibromo-L-phenylalnine exhibit strong anticonvulsant effect in animal models suggesting use of these compounds as a novel class of antiepileptic drugs.[80][81]
Agonists
- 5-Fluorowillardiine – a synthetic modification of willardiine
- AMPA– a synthetic agonist after which the receptor is named
- Domoic acid – a naturally occurring agonist that causes amnesic shellfish poisoning
- Glutamic acid (glutamate) – the endogenous agonist
- Ibotenic acid – a naturally occurring agonist found in Amanita muscaria
- Quisqualic acid – a naturally occurring agonist found in certain species
- Willardiine – a naturally occurring agonist
Positive allosteric modulators
- Aniracetam
- Cyclothiazide
- CX-516
- CX-546
- CX-614
- TAK-653
- CX-717
- Farampator (CX-691, ORG-24448)
- IDRA-21
- LY-404187
- LY-503430[82][83]
- Mibampator (LY-451395)
- ORG-26576
- Oxiracetam
- PEPA
- PF-04958242
- Piracetam
- Pramiracetam
- Tulrampator (S-47445, CX-1632)
Antagonists
- Becampanel
- CNQX
- Dasolampanel
- DNQX
- Fanapanel (MPQX)
- Kaitocephalin
- Kynurenic acid – endogenous ligand
- L-theanine
- NBQX
- 3,5-Dibromo-L-phenylalanine, a naturally occurring halogenated derivative of L-phenylalanine[84]
- Perampanel
- Selurampanel
- Tezampanel
- Zonampanel
Negative allosteric modulators
- Barbiturates (e.g., pentobarbital, sodium thiopental) – non-selective
- Ethanol – non-selective
- ) – non-selective
- GYKI-52466
- Irampanel
- Perampanel
- Talampanel
- PEP1-TGL : GluA1 subunit C-terminus peptide analog that inhibits AMPA receptor incorporation to the postsynaptic density[85][86]
See also
- Arc/Arg3.1
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