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The Journal of Neuroscience, January 18, 2006, 26(3):763-774; doi:10.1523/JNEUROSCI.2489-05.2006

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Cellular/Molecular
Essential Contribution of the Ligand-Binding B/C Loop of PDZ1 and PDZ2 in the Regulation of Postsynaptic Clustering, Scaffolding, and Localization of Postsynaptic Density-95

Mio Nonaka,^1,2 Tomoko Doi,¹ Yoshinori Fujiyoshi,¹ Sayaka Takemoto-Kimura,² and Haruhiko Bito^2,3

¹Department of Biophysics, Kyoto University Graduate School of Science, Kyoto 606-8502, Japan, ²Department of Neurochemistry, University of Tokyo Graduate School of Medicine, Tokyo 113-0033, Japan, and ³Solution-Oriented Research for Science and Technology–Japan Science and Technology, Kawaguchi 332-0012, Japan

Postsynaptic density-95 (PSD-95), a PSD-95/Discs large/zona occludens-1 (PDZ) domain-containing scaffold protein, clusters many signaling molecules near NMDA-type glutamate receptors in the postsynaptic densities. Although the synaptic localization of PSD-95 requires palmitoylation of two cysteines at the N terminus and the presence of at least one PDZ domain, how the clustering of PSD-95 is initiated and regulated remains essentially unknown. To address this issue, we examined PSD-95 clustering in primary cultured hippocampal neurons expressing full-length PSD-95 mutant proteins lacking the ligand-binding ability of PDZ1, PDZ2, and/or PDZ3. The formation of either excitatory or inhibitory synapses was unaffected. Combinations of individual mutations, however, significantly reduced the PSD-95 clustering index, in an approximately additive manner. The sensitivity to 2-bromo-palmitate and latrunculin A, reagents known to affect PSD-95 turnover, was also augmented. Furthermore, the synaptic recruitment of a PSD-95 ligand, synaptic GTPase-activating protein (synGAP), was significantly impaired, whereas the clustering of other scaffolding proteins, such as Homer 1c, Shank/Synamon, and PSD-93/Chapsin-110 was spared. Intriguingly, overexpression of the PSD-95 PDZ1/2/3 mutants caused the PSD-95 clusters to localize away from the dendritic shaft, resulting in the formation of elongated spines, in an inverse correlation with the overall PDZ-ligand affinity. Expression of a mutant synGAP lacking the PDZ-binding motif replicated both the clustering and spine morphology phenotypes. In conclusion, the ligand-binding affinity of the PDZ domains of PSD-95, contributed in part via its interaction with the C-terminal end of synGAP, plays a critical role in titrating the synaptic clustering of PSD-95 and controlling its tight association with the PSD scaffold, thereby affecting synapse maturation.

Key words: PSD-95; clustering; spine; synGAP; NMDA receptor; PDZ domains; binding affinity

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Received June 17, 2005; revised November 18, 2005; accepted November 22, 2005.

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				N. Ageta-Ishihara, S. Takemoto-Kimura, M. Nonaka, A. Adachi-Morishima, K. Suzuki, S. Kamijo, H. Fujii, T. Mano, F. Blaeser, T. A. Chatila, et al. Control of Cortical Axon Elongation by a GABA-Driven Ca2+/Calmodulin-Dependent Protein Kinase Cascade J. Neurosci., October 28, 2009; 29(43): 13720 - 13729. [Abstract] [Full Text] [PDF]

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