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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as

crystallized.[2]

Structure and function

Subunit composition

AMPARs are composed of four types of subunits encoded by different genes, designated as

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.[7]

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 does not in fact cross the membrane at all, but kinks back on itself within the membrane and returns to the intracellular side.[8]
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

PSD-95 owing to incompatible PDZ domains, although they do interact with PSD-95 via stargazin (the prototypical member of the TARP family of AMPAR auxiliary subunits).[11]

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

synaptic transmission in the central nervous system.[18]
The AMPAR's permeability to
equilibrium potential near 0 mV. The prevention of calcium entry into the cell on activation of GluA2-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 GluA2 subunits, then it is susceptible to being blocked in a voltage-dependent manner by a class of molecules called

I/V curve, which means that they pass less outward current than inward current at equivalent distance from the reversal potential.[22] Calcium permeable AMPARs are found typically early during postnatal development on neocortical pyramidal neurons,[22] some interneurons, or in dopamine neurons of the ventral tegmental area after the exposure to an addictive drug.[23]

Alongside

exons to be translated interchangeably, leading to several functionally different subunits from each gene.[24]

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

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 excitatory postsynaptic potential (EPSP) following tetanus. This response is interesting since it is thought to be the physiological correlate for learning and memory in the cell. In fact, it has been shown that, following a single paired-avoidance paradigm in mice, LTP can be recorded in some hippocampal synapses in vivo.[29]

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

CaMKII
, which phosphorylates AMPARs, increasing their single-channel conductance.

AMPA receptor trafficking

Regulation of AMPAR trafficking to the postsynaptic density in response to LTP-inducing stimuli
Regulation of AMPAR trafficking to the postsynaptic density in response to LTP-inducing stimuli

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 (

Mitogen-activated protein kinases (MAPK).[31] 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.[10]
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 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).

SAP97).[36] 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.[37] 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.[38]

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

glutamate.[43] 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.[44] Therefore, it is possible that myosin may drive the lateral movement of AMPA receptors in the perisynaptic region to the PSD. Transmembrane AMPA receptor regulatory proteins (TARPs) are a family proteins that associate with AMPA receptors and control their trafficking and conductance.[45] CACNG2 (Stargazin) is one such protein and is found to bind AMPA receptors in the perisynaptic and postsynaptic regions.[46] The role of stargazin in trafficking between the perisynaptic and postsynaptic regions remains unclear; however, stargazin is essential for immobilizing AMPA receptors in the PSD by interacting with PSD-95.[47] PSD-95 stabilizes AMPA receptors to the synapse and disruption of the stargazin-PSD-95 interaction suppressed synaptic transmission.[11]

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

plasma membrane. Recycling endosomes within the dendritic spine contain pools of AMPA receptors for such synaptic reinsertion.[50] Two distinct pathways exist for the trafficking of AMPA receptors: a regulated pathway and a constitutive pathway.[51][52]

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

LTD-Induced AMPA Receptor Endocytosis
LTD-induced endocytosis of AMPA receptors

voltage-dependent calcium channels, agonism of AMPA receptors, and administration of insulin, suggesting general calcium influx as the cause of AMPAR endocytosis.[64] Blockage of PP1 did not prevent AMPAR endocytosis, but antagonist application to calcineurin led to significant inhibition of this process.[65]

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.

Kainic acid, a convulsant that is widely used in epilepsy research induces seizures, in part, via activation of AMPA receptors[73]

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]

ezogabine, the FDA recommended that perampanel be classified by the Drug Enforcement Administration
(DEA) as a scheduled drug. It has been designated as a Schedule 3 controlled substance.

Decanoic acid acts as a non-competitive AMPA receptor antagonist at therapeutically relevant concentrations, in a voltage- and subunit-dependent manner, and this is sufficient to explain its antiseizure effects.[78] This direct inhibition of excitatory neurotransmission by decanoic acid in the brain contributes to the anticonvulsant effect of the medium-chain triglyceride ketogenic diet.[78] Decanoic acid and the AMPA receptor antagonist drug perampanel act at separate sites on the AMPA receptor, and so it is possible that they have a cooperative effect at the AMPA receptor, suggesting that perampanel and the ketogenic diet could be synergistic.[78][79]

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

Glutamate, the endogenous agonist
of the AMPAR.
AMPA, a synthetic agonist of the AMPAR.

Positive allosteric modulators

Main article: AMPA receptor positive allosteric modulator

Antagonists

Negative allosteric modulators

Perampanel, a negative allosteric modulator of the AMPAR used to treat epilepsy.

See also

  • Arc/Arg3.1

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External links
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