, 2010 and Yim et al., 2010), whereas shedding of the

adaptors requires degradation of PI(4,5)P2 via the action of PI(4,5)P2 phosphatases, primarily synaptojanin (Cremona et al., 1999 and Hayashi et al., 2008). These reactions are assisted by a variety of accessory factors, which prominently include members of the BAR domain-containing protein superfamily (Frost et al., 2009 and Peter et al., 2004). BAR domains undergo dimerization to generate membrane-associated modules, which most typically have a crescent shape with a basic, membrane-binding surface at their convex surface. These modules bind curved bilayers and function as curvature sensors and/or inducers (Antonny, 2006, Frost et al., 2009 and Peter et al., 2004). An abundant endocytic JAK phosphorylation BAR domain-containing protein is endophilin A (referred to henceforth as endophilin), which is conserved from yeast (Rvs167) to mammals, where it is encoded signaling pathway by three different genes (SH3GL2, SH3GL1, and SH3GL3 encoding endophilin 1, 2, and 3 respectively) (de Heuvel et al., 1997 and Ringstad et al., 1997). The N-terminal BAR domain of endophilin

is followed, after a short sequence, by a C-terminal SH3 domain whose major interactors in the nervous system are dynamin and synapotojanin. The three endophilins have different patterns of expression but are all expressed in the brain, with endophilin 1 being the most abundant isoform (de Heuvel et al., 1997, Ringstad et al., 1997 and Ringstad et al., 2001). Although endophilin has been extensively investigated, its precise function remains debated. Its molecular properties suggest a role in coordinating CCP neck constriction,

via its BAR domain, with the recruitment of both dynamin (to mediate CCP fission from the plasma membrane) and synaptojanin (to help in uncoating), via its SH3 domain. Indeed, endophilin is recruited to CCPs shortly found before fission (Perera et al., 2006) and independently of dynamin recruitment (Ferguson et al., 2009). Microinjection experiments at the lamprey giant axon and genetic studies in Drosophila and C. elegans have explored endophilin functions at synapses. Although initial experiments in the lamprey model had suggested both early and late actions of endophilin in clathrin-mediated budding ( Ringstad et al., 1999), subsequent studies have indicated primarily late actions ( Dickman et al., 2005, Gad et al., 2000, Schuske et al., 2003, Verstreken et al., 2002 and Verstreken et al., 2003), consistent with the recruitment of endophilin at CCPs shortly before fission. An accumulation of clathrin-coated vesicles (CCVs), reflecting a major role in uncoating, was the predominant consequence of the disruption of endophilin function in these studies, but a buildup of budding intermediates was also reported, consistent with a role of endophilin in fission ( Gad et al., 2000, Schuske et al., 2003, Verstreken et al., 2002 and Verstreken et al., 2003).