Glutamate is the major excitatory neurotransmitter and modulates its effects via ionotropic and metabotropic receptors which are different in their molecular, biochemical, pharmacological and physiological properties¹.

The ionotropic ligand-gated ion channel glutamate receptors are classified into three major subtypes, AMPA, kainate and NMDA receptors according to their selective agonist.

AMPA receptors consist of four closely related genes with about 70% homology that encode the four subunits GluR1-4. Their expression is known to be developmentally regulated² and are also known to undergo alternative splicing. In fact, all four receptors have two splice variants, termed flip and flop, in an extracellular region adjacent to the M4 transmembrane region³. These splice variants are also developmentally regulated such that flip is expressed before birth and remains highly expressed throughout adulthood whereas flop expression is postnatal and reaches flip’s level in adulthood⁴.

In addition to their expression regulation, flip and flop also differ in their activation/inactivation kinetics. Each AMPA receptor contains 3 membrane spanning domains (M1, M3 and M4), while the fourth hydrophobic domain (M2) is a reentering cytoplasmic loop that forms part of the channels pore¹. Different stoichiometries of these receptors form tetrameric structures to eventually form functional receptors⁵.

AMPA receptors are highly expressed in the brain. However, the GluR4 subunit is present in lower amounts in the CNS, except in the reticular thalamic neuclei and the cerebellum¹.

The primary depolarization in glutamate neurotransmission is mediated by AMPA receptors, which are also key players in synaptic plasticity, learning and memory formation. The cellular distribution and post-translational modifications like phosphorylation are important for the activity of AMPA receptors and are thought to play a role in the long lasting and activity-dependent changes in synaptic strength^6-9.