The a1 isoform is found in synaptic vesicle membranes ( Morel et al., 2003), which is also present in the presynaptic membrane. In addition to having a role in acidifying intracellular membrane-bound compartments (Figure 1B), Zhang et al. provide evidence that vATPase speeds up endocytosis by alkalinizing the cytoplasm

(Figure 1C). This protein, or several of its subunits, may also have other functions related to exocytosis. The V0 domain of the vATPase interacts with another protein of the synaptic vesicle membrane, synaptobrevin (Figure 1D), one of the core SNARE proteins, and with the SNARE complex in different model systems (Galli et al., 1996 and Morel et al., 2003). Recently, Di Giovanni et al. (2010) have demonstrated a Ca2+/calmodulin regulated direct protein-protein interaction in synaptic vesicles between synaptobrevin (the v-SNARE) and the c subunit of V0. Furthermore, PI3K inhibitor the perturbation of this interaction produces a substantial decrease in the probability www.selleckchem.com/products/BEZ235.html of neurotransmitter release. It has been suggested ( Di Giovanni et al., 2010) that the cis interaction between synaptobrevins and the c subunits of the V0 domain may prevent the formation of the SNARE complex, which implies that dissociation of this complex (regulated by Ca2+/calmodulin)

must precede fusion. Under this hypothesis it may also be possible that the c subunits may help orient synaptobrevin molecules as they enter SNARE complexes with SNAP-25 and syntaxin. More than two decades ago, Israel et al. (1986) reported the isolation of a proteolipid pore complex (c subunit), which they named mediatophore, from synaptosomes formed from Torpedo electroplaques, and they

suggested that it mediates calcium-dependent ACh release. Since then, additional evidence has accumulated that the V0 domain of the vATPase participates in membrane fusion downstream of SNAREs ( Peters et al., 2001 and Hiesinger et al., 2005). One idea is that after a vesicle is fully loaded with neurotransmitter, the cytoplasmic V1 domain dissociates from the intramembrane V0 domain of the vATPase. The naked V0 domain can then dimerize with another V0 domain located in the plasma membrane, and (like a gap junction) create a pore Phosphoprotein phosphatase that allows the passage of neurotransmitter from vesicle lumen to synaptic cleft ( Figure 1E). Recent reports support this hypothesis. For example, in a loss-of-function mutation in Drosophila V0 domain, neurotransmitter loading and synaptic vesicle acidification were not altered, while synaptic vesicle fusion with the presynaptic membrane was blocked downstream of the SNARE complex formation ( Hiesinger et al., 2005). It is been proposed that the SNARE complex helps to align the two opposed V0 proteolipid rings, which, when joined together, participate in the formation of the fusion pore.