All synaptotagmin-controlled fusion reactions appear to require complexin as a cofactor (e.g., see Reim et al., 2001, Cai et al., 2008, Jorquera et al., 2012 and Cao et al., 2013). It seems likely that all Ca2+-triggered exocytosis depends on synaptotagmin Ca2+ sensors and complexins and that different synaptotagmins contribute to the specificity of exocytosis pathways. Ultrafast neurotransmitter release in response to an action potential can only be achieved by tethering Ca2+ channels to docked c-Met inhibitor and primed synaptic
vesicles at the active zone. A large protein complex whose central components are three multidomain proteins called RIM, RIM-BP, and Munc13 mediates the docking and priming of synaptic vesicles at the active zone and recruits Ca2+ channels to docked and primed vesicles (Kaeser et al., 2011). Thus, a single protein
complex www.selleckchem.com/products/pf-06463922.html organizes release sites (Figure 1; reviewed in Südhof, 2013). RIM (for Rab3-interacting molecule; Wang et al., 1997) binds to small Rab3 and Rab27 GTP-binding proteins that are localized on synaptic vesicles, thereby docking the vesicles (Gracheva et al., 2008, Kaeser et al., 2011, Han et al., 2011 and Fernández-Busnadiego et al., 2013). RIM also binds to Munc13 (no relation to Munc18; Brose et al., 1995 and Betz et al., 2001), thereby activating Munc13 (Deng et al., 2011). Munc13 is a priming factor (Augustin et al., 1999) that catalyzes the conformational switch of syntaxin-1 from closed to open, promoting SNARE complex assembly (Richmond et al., 2001 and Ma et al., 2013). RIM binding to both Munc13 and Rab3/27 is mediated by a composite
N-terminal domain that contains a Munc13-binding zinc finger surrounded by Rab3-binding α helices (Dulubova et al., 2005 and Lu et al., 2006). Ca2+ channels need to be localized adjacent to docked and primed vesicles for fast coupling of an action potential to Ca2+-triggered exocytosis. Ca2+ channels are generally positioned less than 100 nm away from docked vesicles (Eggermann et al., 2012). RIM and the RIM-interacting molecule RIM-BP (Wang et al., 2000) both bind to Ca2+ channels in addition to binding to each other (Kaeser et al., 2011). Deletion of RIM in mice (Kaeser et al., 2011, Kaeser et al., 2012 and Han et al., 2011) and found of RIM-BP in flies (Liu et al., 2011) causes a loss of Ca2+ channels from presynaptic active zones and a decrease in Ca2+ influx. These data show that RIM and RIM-BP collaborate to recruit Ca2+ channels to release sites. Thus, in a parsimonious design, a single protein complex that contains RIM as a central element mediates the colocalization of all critical proteins to the active zone. This protein complex localizes synaptic vesicles, Ca2+ channels, and vesicle priming factors next to release sites, thereby allowing fast coupling of an action potential to neurotransmitter release (Figure 1C).