Involvement of unique leucine-zipper motif of PSD-Zip45 (Homer 1c/vesl-1L)in group 1 metabotropic glutamate receptor clustering

Several scaffold proteins for neurotransmitter receptors have been identifi ed as candidates for receptor targeting. However, the molecular mechanism u nderlying such receptor clustering and targeting to postsynaptic specializa tions remains unknown. PSD-Zip45 (also named Homer 1c/vesl-1L) consists of the NH2 terminus containing the enabled/VASP homology 1 domain and the COOH terminus containing the leucine zipper. Here, we demonstrate immunohistoch emically that metabotropic glutamate receptor 1 alpha (mGluR1 alpha) and PS D-Zip45/Homer Ic are colocalized to synapses in the cerebellar molecular la yer but not in the hippocampus. In cultured hippocampal neurons, PSDZip45/H omer1c and N-methyl-D-aspartate receptors are preferentially colocalized to dendritic: spines. Cotransfection of mGluR1 alpha or mGluR5 and PSD-Zip45/ Homer Ic into COS-7 cells results in mGluR clustering induced by PSD-Zip45/ Homer Ic. An in vitro multimerization assay shows that the extreme COOH-ter minal leucine zipper is involved in self-multimerization of PSD-Zip45/Homer Ic. A clustering assay of mGluRs in COS-7 cells also reveals a critical ro le of this leucine-zipper motif of PSD-Zip45/Homer Ic in mGluR clustering. These results suggest that the leucine zipper of subsynaptic scaffold prote in is a candidate motif involved in neurotransmitter receptor clustering at the central synapse.