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Essential role of phosphoinositide metabolism in synaptic vesicle recycling.
Growing evidence suggests that phosphoinositides play an important role in membrane traffic. A polyphosphoinositide phosphatase, synaptojanin 1, was identified as a major presynaptic protein associated with endocytic coated intermediates. We report here that synaptojanin 1-deficient mice exhibit neurological defects and die shortly after birth. In neurons of mutant animals, PI(4,5)P2 levels are increased, and clathrin-coated vesicles accumulate in the cytomatrix-rich area that surrounds the synaptic vesicle cluster in nerve endings. In cell-free assays, reduced phosphoinositide phosphatase activity correlated with increased association of clathrin coats with liposomes. Intracellular recording in hippocampal slices revealed enhanced synaptic depression during prolonged high-frequency stimulation followed by delayed recovery. These results provide genetic evidence for a crucial role of phosphoinositide metabolism in synaptic vesicle recycling.
Animals, Cell-Free System, Cerebral Cortex, Coated Pits, Cell-Membrane, Endocytosis, Enzyme Inhibitors, Exons, Hippocampus, Membrane Potentials, Mice, Mice, Knockout, Microscopy, Electron, Nerve Endings, Nerve Tissue Proteins, Neurons, Phosphatidylinositols, Phosphoric Monoester Hydrolases, Synaptic Vesicles
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