, 2013). Such acute manipulations severely impaired not only synchronous but also asynchronous release in hippocampal neurons (Figure 4). Consistent

with the studies in PC12 and primary chromaffin cells, this result suggests that effectively all Ca2+-triggered neurotransmitter release is mediated by a synaptotagmin. Moreover, this result agrees with studies indicating that Syt7 functions as a Ca2+ sensor in neuroendocrine secretion and in lysosome exocytosis (Shin et al., 2002, Chakrabarti et al., 2003, Fukuda et al., 2004, Tsuboi and Fukuda, 2007, Schonn et al., 2008, Gustavsson et al., 2008, Gustavsson et al., 2009, Enzalutamide chemical structure Li et al., 2009 and Segovia et al., 2010). Finally, a role for Syt7 as a Ca2+ sensor in synaptic exocytosis agrees well with the similar Ca2+-binding properties and Ca2+-dependent phospholipid- and

syntaxin-binding properties of Syt1 and Syt7 (Li et al., 1995 and Sugita et al., 2002). However, Syt7 exhibits two puzzling properties. First, in neurons Syt7 is not detectable in synaptic vesicles but is at least partly localized to the plasma membrane (Sugita et al., 2001 and Takamori et al., 2006). This is puzzling given the localization of Syt7 to secretory vesicles selleck chemical in nonneuronal cells (Chakrabarti et al., 2003, Fukuda et al., 2004, Schonn et al., 2008, Gustavsson et al., 2008 and Gustavsson et al., 2009). Second, whereas in all vesicular synaptotagmins tested up to date, the C2B domain Ca2+-binding sites are essential for Ca2+ stimulation of exocytosis and the C2A domain Ca2+-binding sites only assist in Ca2+ triggering of exocytosis (e.g., see Mackler et al., 2002, Nishiki and Augustine, 2004, Shin et al., 2009, Cao et al., 2011 and Lee

et al., 2013), in Syt7 the C2A domain Ca2+-binding sites were essential for asynchronous release and the C2B domain Ca2+-binding sites were dispensable (Bacaj et al., 2013). The differences in the localization and the relative C2 domain functions between Syt1 and Syt7 may be related to each other, and the plasma membrane localization Parvulin of Syt7 may also explain, at least in part, why Syt7 is generally less effective than Syt1 in triggering exocytosis. Alternatively, it is possible that a small amount of Syt7 is present on synaptic vesicles, and its relatively low Ca2+-triggering efficiency is due to its poor synaptic vesicle-sorting efficiency. The recent Syt7 results suggest that different synaptotagmins collaborate and compete with each other as Ca2+ sensors for release and expand the finding that Syt1 is also coexpressed with Syt2 or Syt9 in some synapses where these synaptotagmins also complement each other physiologically (Xu et al., 2007 and Pang et al., 2006b). In the nonphysiological situation of a Syt1 or Syt2 knockout synapse, the observed remaining Ca2+-dependent release may be more complex than simply allowing Syt7 function to become manifest (Figure 5).