Glutamate receptor-interacting protein

Glutamate receptor-interacting protein (GRIP) refers to either a family of proteins that bind to the glutamate receptor or specifically to the GRIP1 protein within this family. Proteins in the glutamate receptor-interacting protein (GRIP) family have been shown to interact with GluR2, a common subunit in the AMPA receptor. This subunit also interacts with other proteins such as protein interacting with C-kinase1 (PICK1) and N-ethylmaleimide-sensitive fusion protein (NSF). Studies have begun to elucidate its function; however, much is still to be learned about these proteins.

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 central nervous system. By using GFP (green fluorescent protein) antibodies that correspond to the GRIP protein, researchers were able to use fluorescence 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 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.

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