Subunit-specific trafficking mechanisms regulating the synaptic expression of Ca(2+)-permeable AMPA receptors

AMPA receptors are the main excitatory neurotransmitter receptor in the brain, and hence regulating the number or properties of synaptic AMPA receptors brings about critical changes in synaptic transmission. Synaptic plasticity is thought to underlie learning and memory, and can be brought about by decreasing or increasing the number of AMPA receptors localised to synaptic sites by precisely regulating AMPA receptor trafficking. AMPA receptors are tetrameric assemblies of subunits GluA1-4, and the vast majority are GluA1/2 and GluA2/3 heteromers. The inclusion of GluA2 subunit is critical because it renders the AMPA receptor channel impermeable to Ca(2+) ions. The vast majority of synaptic AMPA receptors in the brain contain GluA2, but relatively recent discoveries indicate that an increasing number of specific forms of synaptic plasticity involve not only an alteration of the number of synaptic AMPA receptors, but also changes to their GluA2 content. The resulting change in AMPA receptor Ca(2+) permeability clearly has profound consequences for synaptic transmission and intracellular signalling events. The subunit-specific trafficking mechanisms that cause such changes represent an emerging field of research with implications for an increasing number of physiological or pathological situations, and are the topic of this review.