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The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, AMPAR, or quisqualate receptor) is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic 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 discovered by Tage Honore and colleagues at the School of Pharmacy in Copenhagen, and published in 1982 in the Journal of Neurochemistry (Honore T; Lauridsen J; Krogsgaard-Larsen P. The binding of [3H]AMPA, a structural analogue of glutamic acid, to rat brain membranes, Journal of Neurochemistry, 1982, 38, 173-178). AMPARs are found in many parts of the brain and are the most commonly found receptor in the nervous system.


Structure and Function


Subunit Composition

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.[1][2][3] Most AMPARs are heterotetrameric, consisting of symmetric 'dimer of dimers' of GluR2 and either GluR1, GluR3 or GluR4.[4][5] 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.[5]

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 were four transmembrane domains (parts of the protein that pass through the plasma membrane), proteins interacting with the subunit indicated that the N-terminus was extracellular while the C-terminus was intracellular. 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. Eventually, it was discovered that the second transmembrane domain isn't in fact trans at all, but kinks back on itself within the membrane and returns to the intracellular side (see schematic diagram).[6] 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 to SAP97 through SAP97's class I PDZ domain[7], while GluR2 binds to PICK1[8] and GRIP/ABP. Of note, AMPARs cannot directly bind to the common synaptic protein PSD-95 due to incompatible PDZ domains.

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 is phosphorylated by PKC, and is necessary for long term potentiation (LTP; for GluR1's role in LTP, see below).[9] S831 is phosphorylated by CaMKII during LTP, which helps deliver GluR1-containing AMPAR to the synapse,[10] and increases their single channel conductance.[11] The T840 site was more recently discovered, and has been implicated in LTD.[12] Finally, S845 is phosphorylated by both PKA which regulates its open probability.[13]

Ion Channel Function

Each AMPAR has four sites to which an agonist (such as glutamate) can bind, one for each subunit.[14] The binding site is believed to be formed by the n-tail, and the extracellular loop between transmembrane domains three and four [15]. When an agonist binds, these two loops move towards each other, opening the pore. The channel opens when two sites are occupied[16], and increases its current as more binding sites are occupied[17]. 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[18]. AMPARs open and close quickly, and are thus responsible for most of the fast excitatory synaptic transmission in the central nervous system.[16]

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 certainly 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, 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. The prevention of calcium entry into the cell on activation of GluR2-containing AMPARs is proposed to guard against excitotoxicity.[19]

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 (ie towards the C-terminus of) the 4th membranous domain in all four AMPAR subunits, it determines the speed of desensitisation[20] of the receptor and also the speed at which the receptor is resensitised[21] and the rate of channel closing[22]. The flip form is present in prenatal AMPA receptors, and gives a sustained current in response to glutamate activation.[23]

Synaptic Plasticity

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 100Hz 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 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.[24]

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 Mg2+ ions. NMDARs can only open 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, though, 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.



Positive Allosteric Modulators



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See Also


External links


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