Cupidin/Homerによるポストシナプスの分子構成と形態の調節

抄録

Homer is a postsynaptic scaffold protein with the N-terminal target binding and C-terminal self-assembly domains. Homer multimers likely link their targets, including proteins related to the Glu receptor and Ca²⁺ signaling (mGluR1a/5, Shank, IP3R) and to the actin cytoskeleton (Drebrin and Cdc42), at postsynaptic density (PSD). The Homer family consists of three long-form Homers H1b/c, Cupidin/H2, and H3. A natural dominant-negative, short-form H1a with only the N-terminal domain is also activity-dependently expressed. In hippocampus, H1b/c and Cupidin/H2 predominate in CA1 region, whereas H3 is largely localized in CA2-CA3 region. In cultured hippocampal cells, dendritic clustering and synaptic targeting of long Homers coincide with those of NMDAR and PSD-95 throughout development. Overexpression of long Homers increases mature-shape spines, whereas that of H1a alters PSD target contents and spine morphology. In cerebellum, H1b/c and Cupidin/H2 are concentrated in PSDs of granule cells. In cultured granule cells, their clustered distribution is changed by NMDAR-mediated Ca²⁺ influx, and H1a has a neuroprotective action against excess Glu exposure probably by interfering a target linkage via long Homers, which inhibits NMDAR activity. On the other hand, H3 is exclusively localized in Purkinje cells. mGluR1a binding and dendritic localization of H3 is controlled by its Ca²⁺-dependent phosphorylation states. Thus, Homer is involved in synapse formation and function by regulating molecular organization of PSD and spine morphology. [J Physiol Sci. 2006;56 Suppl:S23]