The molecular pharmacology and cell biology of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors

Abstract

Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) are of fundamental importance in the brain. They are responsible for the majority of fast excitatory synaptic transmission, and their overactivation is potently excitotoxic. Recent findings have implicated AMPARs in synapse formation and stabilization, and regulation of functional AMPARs is the principal mechanism underlying synaptic plasticity. Changes in AMPAR activity have been described in the pathology of numerous diseases, such as Alzheimer's disease, stroke, and epilepsy. Unsurprisingly, the developmental and activity-dependent changes in the functional synaptic expression of these receptors are under tight cellular regulation. The molecular and cellular mechanisms that control the postsynaptic insertion, arrangement, and lifetime of surface-expressed AMPARs are the subject of intense and widespread investigation. For example, there has been an explosion of information about proteins that interact with AMPAR subunits, and these interactors are beginning to provide real insight into the molecular and cellular mechanisms underlying the cell biology of AMPARs. As a result, there has been considerable progress in this field, and the aim of this review is to provide an account of the current state of knowledge.

FIG. 1

Schematic showing the topology of an AMPA receptor subunit. Each subunit consists of an extracellular N-terminal domain, four hydrophobic regions (TM1–4), and an intracellular C-terminal domain. The ligand-binding site is a conserved amino acid pocket formed from a conformational association between the N terminus and the loop linking TM3 and TM4. A flip/flop alternative splice region and R/G RNA editing site are also present within the TM3/TM4 loop. TM2 forms an intracellular re-entrant hairpin loop which contributes to the cation pore channel and is also the site for Q/R RNA editing in the GluR2 subunit. The intracellular C terminus contains phosphorylation sites and conserved sequences that have been shown to interact with a number of intracellular proteins, for example, PDZ domain-containing proteins and the ATPase NSF.

FIG. 2

Schematic illustrating that phosphorylation of the GluR1 AMPA receptor subunit may act as a bidirectional switch in synaptic plasticity.

FIG. 3

Electron micrograph and corresponding diagram depicting a single excitatory synapse. The electron dense PSD directly opposes the neurotransmitter release sites located on the presynaptic bouton and the spine neck and spine apparatus are clearly defined (reproduced with permission from Fischer et al., 2000).

FIG. 4

3D reconstruction of confocal image stack showing an area of spiny dendrite from a cultured pyramidal hippocampal neuron expressing a variant of GFP. The surface rendering of this reconstruction allows clear visualization of the varied structure of different spines (reproduced courtesy of Dr. M.C. Ashby, MRC Centre for Synaptic Plasticity, University of Bristol). Scale bar 4 μm.

FIG. 5

Simplified schematic diagram illustrating the protein interactions at GluR1 and GluR2 containing AMPA receptors.