SPINOPHILIN, A NOVEL PROTEIN PHOSPHATASE-1 BINDING-PROTEIN LOCALIZED TO DENDRITIC SPINES

Dendritic spines receive the vast majority of excitatory synaptic cont acts in the mammalian brain and are presumed to contain machinery for the integration of various signal transduction pathways, Protein phosp hatase 1 (PP1) is greatly enriched in dendritic spines and has been im plicated in both the regulation of ionic conductances and long-term sy naptic plasticity, The molecular mechanism whereby PP1 is localized to spines is unknown, We have now characterized a novel protein that for ms a complex with the catalytic subunit of PP1 and is a potent modulat or of PP1 enzymatic activity in vitro. Within the brain this protein d isplays a remarkably distinct localization to the heads of dendritic s pines and has therefore been named spinophilin, Spinophilin has the pr operties expected of a scaffolding protein localized to the cell membr ane and contains a single consensus sequence in PSD95/DLG/zo-1, which implies cross-linking of PP1 to transmembrane protein complexes, We pr opose that spinophilin represents a novel targeting subunit for PP1, w hich directs the enzyme to those substrates in the dendritic spine com partment, e.g., neurotransmitter receptors, which mediate the regulati on of synaptic function by PP1.