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The Journal of Neuroscience, August 1, 1998, 18(15):5594-5602

An Essential Role for a Small Synaptic Vesicle-Associated Phosphatidylinositol 4-Kinase in Neurotransmitter Release

Claudia Wiedemann¹, Theo Schäfer¹, Max M. Burger¹, and Talvinder S. Sihra²

¹ Friedrich Miescher-Institute, 4002 Basel, Switzerland, and ² Department of Pharmacology, Royal Free Hospital School of Medicine, University of London, London NW3 2PF, United Kingdom

Glutamate release from nerve terminals is the consequence of Ca²⁺-triggered fusion of small synaptic vesicles with the presynaptic plasma membrane. ATP dependence of neurotransmitter release has been suggested to be founded, in part, on phosphorylation steps preceding membrane fusion. Here we present evidence for an essential role of phosphatidylinositol phosphorylation in stimulated release of neurotransmitter glutamate from isolated nerve terminals (synaptosomes). Specifically, we show that a phosphatidylinositol 4-kinase (PtdIns 4-kinase) activity resides on nerve terminal-derived small synaptic vesicles (SSVs) and that inhibition of the PtdIns 4-kinase activity in intact synaptosomes leads to attenuation of the evoked release of glutamate. The attenuation of transmitter release is reversible and correlates with respective changes in intrasynaptosomal PtdIns 4-kinase activity. Because only the Ca²⁺-dependent release of glutamate is affected, regulation appears to be at the level of exocytosis. Taken together, our data imply a mandatory role for PtdIns 4-kinase and phosphoinositide products in the regulated exocytosis of SSV in mammalian nerve terminals.

Key words: phosphoinositides; glutamate exocytosis; synaptosomes; small synaptic vesicles; phospholipids; lipid kinase; phosphatidylinositol 4-kinase; priming; ATP dependent; calcium dependent; kinase inhibitors

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18155594-09$05.00/0

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