Glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type mediate the fast component of excitatory synaptic transmission in the central nervous system, play an important role in synaptic plasticity and contribute to cell death under excitotoxic conditions. AMPA receptors are tetramers of variable combinations of the receptor subunits GluR1, GluR2, GluR3 and GluR4. These subunits bind to cytoplasmic and transmembrane proteins that control their subcellular distribution. We have used proteomic approaches in order to identify proteins that interact with the GluR4 AMPA receptor subunit. These approaches have led to the identification of five candidate proteins as interactors for GluR4, some of which also interact with the other AMPA receptor subunits. We have biochemically confirmed the interactions, and found evidence of the binding partners colocalization with AMPA receptors in cultured hippocampal neurons. Moreover, some of these interactors modulate cell surface expression of AMPA receptors. AMPA receptor subunits exist in two functionally different isoforms, flip and flop, generated by alternative splicing. We identified transcripts for alternatively spliced isoforms of AMPA receptor subunits which lack both the flip and the flop exons, in hippocampal and retinal cultures. These transcripts originate AMPA receptor subunits lacking the flip/flop cassette, the fourth transmembrane domain and the intracellular C-terminus. Truncated GluR1 associates with full-length GluR1 and exerts a dominant negative effect, giving rise to non-functional receptors. Moreover, truncated GluR1 reaches the cell surface, but is not efficiently targeted to the synapse. Hippocampal neuronal transfection with truncated GluR1 resulted in a significant reduction in apoptotic neuronal death triggered by toxic concentrations of glutamate. Furthermore, mRNA coding for the truncated subunits is increased in some regions of the brain in epileptic rats and in hippocampal neurons submitted to toxic concentrations of glutamate. The existence of truncated AMPA receptor subunits and their upregulation under hyperexcitability conditions may constitute an intrinsic neuroprotective mechanism.