A N and a NARSAD grant from the Brain and Behavior

Resea

A.N. and a NARSAD grant from the Brain and Behavior

Research Fund to B.E.H. C.-Y.Z. and K.W.R. were supported by the Intramural Research Program of NINDS. Y.H.S. was supported by the Basic Science Research Program (2011-0011694) and MRC (2012048183) through the National Research Foundation GSK-3 phosphorylation of Korea. “
“Phosphoinositides are important cellular signaling lipids, but they are present at very low concentrations in the nervous system (Di Paolo and De Camilli, 2006). While based on their phosphorylation status, seven different phosphoinositides are known at the presynaptic terminal, and phosphatidylinositol 4,5 bisphosphate (PI(4,5)P2) has been best studied and is involved in a growing number of processes, including the spatial and temporal recruitment of cytosolic proteins that mediate synaptic vesicle cycling and synaptic growth (Cremona et al., 1999; Khuong et al., 2010; Martin, 2012; Verstreken et al., 2009; Wenk et al., 2001). PI(4,5)P2-dependent

recruitment of proteins to specific membrane domains occurs via specific motifs but also by electrostatic interactions with unstructured protein regions that are rich in basic amino acids, inducing the formation of protein-lipid Duvelisib mw microdomains (Heo et al., 2006; van den Bogaart et al., 2011). In contrast to PI(4,5)P2, phosphatidylinositol 3,4,5 trisphosphate (PI(3,4,5)P3) is much less abundant (Clark et al., 2011) and the lipid has been implicated in the clustering of glutamate receptors and postsynaptic density protein-95 in the plasma membrane of postsynaptic terminals (Arendt et al., 2010); however, the mechanism was not elucidated. Contrary to this postsynaptic role, the function of PI(3,4,5)P3 at presynaptic terminals remains

enigmatic. Here, using transgenic imaging probes based on split Venus, we show that PI(3,4,5)P3 concentrates in discrete foci and that these foci largely colocalize with presynaptic release sites that are also rich in Syntaxin1A, a SNARE protein essential for synaptic vesicle fusion (Gerber et al., 2008; Schulze et al., 1995). Non-specific serine/threonine protein kinase Although phosphorylated phosphoinositides have been implicated in synaptic vesicle endocytosis by interacting with adaptors and other proteins (Cremona et al., 1999; Di Paolo et al., 2004), we find that, unlike reducing PI(4,5)P2 availability, reducing PI(3,4,5)P3 levels at presynaptic terminals does not result in significant defects in synaptic vesicle formation. Instead, based on in vitro and in vivo assays, we find that PI(3,4,5)P3 is critical to induce the clustering of Syntaxin1A and this feature is dependent on the positively charged residues in the Syntaxin1A juxtamembrane domain, suggesting that electrostatic interactions mediate this effect. Either reducing PI(3,4,5)P3 availability or expressing a Syntaxin1A with a mutated juxtamembrane domain results in reduced neurotransmitter release, similar to partial loss of Syntaxin1A function.

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