We found that glyceraldehyde-3-phosphate dehydrogenase directly interacts with the amino-terminal domain of the AMPA receptor GluR2 subunit, and determined this interaction is located specifically in a 30 amino acid long region. This association is involved in the regulation of AMPA receptor trafficking and the AMPA receptor-mediated cell death.As both AMPA receptors and glyceraldehyde-3-phosphate dehydrogenase are important for several neurological and neuropsychiatric disease states, identifying this molecular machinery may provide novel therapeutic strategies to combat these disease entities.AMPA receptors carry the fast postsynaptic current after the presynaptic glutamate release, which is important for the initial excitation of neurons. Protein-protein interactions have been suggested to be involved in the regulation of AMPA receptors population and function. The overall goal of this research was to examine the novel protein-protein interaction between the amino-terminus of the AMPA receptor and glyceraldehyde-3-phosphate dehydrogenase and the molecular mechanisms for the regulation of AMPA receptors.