Glutamate receptor (GluR) 82 selectively expressed in cerebellar Purkinje cells plays key roles in synapse formation, long-term depression and motor learning. We propose that GluR delta 2 regulates synapse formation by making a physical linkage between the active zone and postsynaptic density. To examine the issue, GluR delta 2-transfected 293T cells were cultured with cerebellar neurons. We found numerous punctate signals for presynaptic markers on the surface of 293T cells expressing GluR delta 2. The presynaptic specializations induced by GluR delta 2 were capable of exo- and endocytosis as indicated by FM1-43 dye labeling. Replacement of the extracellular N-terminal domain (NTD) of GluR delta 2 with that of the AMPA receptor GluR alpha 1 abolished the inducing activity. The NTD Of GluR delta 2 fused to the immunoglobulin constant region Successfully induced the accumulation of presynaptic specializations on the surface of beads bearing the fusion protein. These results suggest that GluR delta 2 triggers presynaptic differentiation by direct interaction with presynaptic components through the NTD. (c) 2008 Elsevier Inc. All rights reserved.