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The Journal of Neuroscience, February 1, 2002, 22(3):803-814

Delphilin: a Novel PDZ and Formin Homology Domain-Containing Protein that Synaptically Colocalizes and Interacts with Glutamate Receptor 2 Subunit

Yohei Miyagi¹, Tetsuji Yamashita², Masahiro Fukaya³, Tomoko Sonoda², Toshiaki Okuno⁴, Kazuyuki Yamada³, Masahiko Watanabe³, Yoji Nagashima¹, Ichiro Aoki¹, Kenji Okuda², Masayoshi Mishina^{4, 5}, and Susumu Kawamoto²

Departments of ¹ Pathology and ² Bacteriology, Yokohama City University School of Medicine, Yokohama 236-0004, Japan, ³ Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan, ⁴ Department of Molecular Neurobiology and Pharmacology, University of Tokyo Graduate School of Medicine, Tokyo 113-0033, Japan, and ⁵ Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Saitama 332-0012, Japan

The glutamate receptor 2 (GluR2) subunit is selectively expressed in cerebellar Purkinje cells and plays an important role in cerebellar long-term depression, motor learning, motor coordination, and synapse development. We identified a novel GluR2-interacting protein, named Delphilin, that contains a single PDZ domain and formin homology (FH) domains FH1 and FH2 plus coiled-coil structure. As far as we know, this is the first reported protein that contains both PDZ and FH domains. Yeast two-hybrid and surface plasmon resonance (SPR) analyses indicated that Delphilin interacts with the GluR2 C terminus via its PDZ domain. This was also supported by coimmunoprecipitation experiments using a heterologous expression system in mammalian cells. Yeast cell and SPR analyses also demonstrated the possibility that the FH1 proline-rich region of Delphilin interacts with profilin, an actin-binding protein, and with the Src homology 3 domain of neuronal Src protein tyrosine kinase. In situ hybridization demonstrated the highest expression of Delphilin mRNA in Purkinje cells. Delphilin polypeptide was highly enriched in the synaptosomal membrane fraction of the cerebellum and coimmunoprecipitated with the GluR2 subunit. The post-embedding immunogold technique demonstrated that Delphilin is selectively localized at the postsynaptic junction site of the parallel fiber-Purkinje cell synapse and colocalized with GluR2. Thus, Delphilin is a postsynaptic scaffolding protein at the parallel fiber-Purkinje cell synapse, where it may serve to link GluR2 with actin cytoskeleton and various signaling molecules.

Key words: glutamate receptor 2 subunit; cerebellum; Purkinje cell; parallel fiber synapses; yeast two-hybrid; surface plasmon resonance; PDZ domain; FH domain; post-embedding immunogold labeling

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Copyright © 2002 Society for Neuroscience  0270-6474/02/223803-12$05.00/0

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