Functional Analysis of Molecular Mechanisms of Presynaptic Metabotropic Glutamate Receptors

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A number of PDZ domain-containing proteins have been reported to interact with target proteins via the recognition of a PDZ-binding motif located at their C-terminal regions. In the cases of receptor-associated proteins, they may play distinct roles in receptor signalling. In order to understand the function of metabotropic glutamate receptors (mGluRs), we searched for receptor-associated proteins and identified a PDZ domain-containing protein, tamalin, that interacts with group 1 mGluRs.Tamalin is a scaffold protein that comprises multiple protein-interacting domains. It possesses a PDZ domain, a leucine-zipper region, a proline-rich region, and a carboxyl-terminal PDZ binding motif. The PDZ domain of tamalin interacts with the carboxyl termini of group 1 and group 2 mGluRs and GABAB2 receptor, whereas the leucine-zipper region binds to the coiled coil region of guanine nucleotide exchange factor cytohesins. Tamalin promotes intracellular trafficking and cell surface expression of group 1 mGluRs in COS-7 cells and cultured hippocampal neurons through the interaction with cytohesins.Tamalin interacts with typical postsynaptic scaffold proteins, PSD-95, S-SCAM, and SAPAP1/3, and the tamalin-mediated different assembly of postsynaptic scaffold proteins may have a distinct and important role in organizing a postsynaptic signal-processing machinery specific for group 1 mGluRs. Tamalin also associates with Mint2 and CASK, which are involved in protein transport.In summary, our study shows that tamalin interacts with many important scaffold proteins involved in postsynaptic organization and protein trafficking in neurons. This indicates that tamalin may participate in receptor clustering, trafficking, and intracellular signalling.