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Discovery and History of GRIP 1
The discovery of the Glutamate Receptor Interacting Protein (GRIP-1) came as a result of the observation that Glutamate Receptors, such as the NMDA receptor, cluster during a synapse. Shortly after this observation, researchers identified a region on the C-terminal region of NMDA receptors called the tSXV motif that has the ability to bind to the PDZ domain of the PSD-95 protein.

Research on NMDA receptor localization paved the way for research on non-NMDA receptors such as AMPA receptors. Similar to NMDA receptors, it was discovered that AMPA receptors localize in the synaptic terminal of neurons in the CNS. By using GFP (green fluorescent protein) antibodies that correspond to the GRIP protein, researchers were able to use florescence to determine the location of GRIP in hippocampal neurons. Another GFP antibody was then used to label the GluR2 subunit of AMPA receptors. By using immunocytochemistry and comparing the location of GRIP and AMPA receptors it was determined that GRIP and AMPA receptors experience colocalization in hippocampal neurons. These findings confirmed the initial hypothesis that the GRIP protein plays an important role in binding AMPA receptors to excitatory synapses.

The structure of GRIP contains seven PDZ domains and binds to the C-terminus of the GluR2 subunit of AMPA receptors. Although the number of PDZ domains is different for the proteins PSD-95 and GRIP, the PDZ domain is a common structural motif in proteins that help mediate protein-protein interactions. The AMPA receptor amino acid sequence that the GRIP protein binds to is ESVKI. The conserved serine amino acid in the C- terminus of both AMPA and NMDA receptors suggests that it plays an important role in facilitating the interaction for GRIP and PSD-95.