AMPA Receptors

Structure of the AMPA Receptor

Structure of the GluA2 subunit. The subunit is used to illustrate the structural properties of the AMPA receptor subunits. The N-terminus is extracellular and C-terminus is intracellular. Splice variation occurs in the 'Flip/Flop' region, giving two variants for each gene sequence. The C-terminus contains binding regions for AP2, NSF and PDZ proteins such as PICK1 and GRIP.

AMPA receptors mediate fast synaptic transmission in the CNS and are composed of subunits GluA1-4, products from separate genes. Like all the ionotropic glutamate receptors subunits, GluA subunits have an extracellular N-terminus and an intracellular C-terminus (illustrated by GluA2 subunit). The ligand binding domain is made up from N-terminal region S1 and S2.

All AMPA receptor subunits exist as two splice variants, flip and flop. The alternative splice cassette is found at the C-terminal end of the loop between TMIII and TMIV. Although the change in the receptor subunits is small (only a few amino acids are changed), the effect can be quite dramatic, resulting in altered desensitisation kinetics.

Native AMPA receptor channels are impermeable to calcium, a function controlled by the GluA2 subunit. The calcium permeability of the GluA2 subunit is determined by the post-transcriptional editing of the GluA2 mRNA, which changes a single amino-acid in the TMII region from glutamine (Q) to arginine (R). This is the so called Q/R editing site - GluA2(Q) is calcium permeable whilst GluA2(R) is not. Almost all the GluA2 protein expressed in the CNS is in the GluA2(R) form, giving rise to calcium impermeable AMPA receptors. This, along with the interactions with other intracellular proteins, makes GluA2 perhaps the most important AMPA receptor subunit.

Functions of AMPA Receptors

AMPA receptors are responsible for the bulk of fast excitatory synaptic transmission throughout the CNS and their modulation is the ultimate mechanism that underlies much of the plasticity of excitatory transmission that is expressed in the brain. Increasing the post-synaptic response to a stimulus is achieved either through increasing the number of AMPA receptors at the post-synaptic surface or by increasing the single channel conductance of the receptors expressed. This was shown to be the basis of LTP mechanisms (Benke et al 1998). More recently, it has become clear that these two apparently different mechanisms to increase AMPA receptor response can be combined, with the insertion of Ca2+ permeable AMPA receptors that have a high conductance in response to tetanic stimulation. Thus the overall conductance of a synapse may be increased by receptor insertion rather than modification of existing receptors (Terashima et al 2004; Plant et al 2006).

The C-terminus of the GluA2 subunit contains binding sites for a large number of interacting proteins such as NSF, AP2, as well as a terminal PDZ domain that binds PICK1 and GRIP, while the GluA1 subunit interacts with SAP97. The effects of these protein-protein interactions is crucial in localisation and trafficking of these receptors so that they can fulfill their roles in plasticity.