AN ESSENTIAL ROLE FOR A SMALL SYNAPTIC VESICLE-ASSOCIATED PHOSPHATIDYLINOSITOL 4-KINASE IN NEUROTRANSMITTER RELEASE

Glutamate release from nerve terminals is the consequence of Ca2+-trig gered fusion of small synaptic vesicles with the presynaptic plasma me mbrane. ATP dependence of neurotransmitter release has been suggested to be founded, in part, on phosphorytation steps preceding membrane fu sion. Here we present evidence for an essential role of phosphatidylin ositol phosphorylation in stimulated release of neurotransmitter gluta mate from isolated nerve terminals (synaptosomes). Specifically, we sh ow that a phosphatidylinositol 4-kinase (PtdIns 4-kinase) activity res ides on nerve terminal-derived small synaptic Vesicles (SSVs) and that inhibition of the PtdIns 4-kinase activity in intact synaptosomes lea ds to attenuation of the evoked release of glutamate. The attenuation of transmitter release is reversible and correlates with respective ch anges in intrasynaptosomal PtdIns 4-kinase activity Because only the C a2+-dependent release of glutamate is affected, regulation appears to be at the level of exocytosis. Taken together, our data imply a mandat ory role for PtdIns 4-kinase and phosphoinositide products in the regu lated exocytosis of SSV in mammalian nerve terminals.