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    • At the molecular level AZ scaffold

    2022-06-09

    At the molecular level AZ scaffold proteins including piccolo and bassoon have been shown to directly or indirectly associate with endocytic and actin-binding proteins such as ABP1 (Fenster et al., 2003), profilin, and GIT (Podufall et al., 2014) (Fig. 2B). ABP1 and profilin, via regulating F-actin, likely contribute to the efficiency of SV endocytosis, which requires formation of linear iso 1 filaments nucleated by formin activity (Soykan et al., 2017, Wu et al., 2016). GIT1/2 and its Drosophila ortholog dGIT associate with piccolo and liprins at the periphery of the AZ (Kim et al., 2003) and are required for the recruitment of the synaptotagmin-specific sorting adaptor stonin 2/stoned B to sites of presynaptic endocytosis and SV reformation (Podufall et al., 2014). Other proteins that may link the CAZ to sites of SV exo-endocytosis include intersectins, SH3 domain-containing scaffold proteins that associate with both exocytic (e.g. SNAP-25) and endocytic proteins (e.g. dynamin, synaptojanin, Eps15, FCHo, AP-2) (Pechstein et al., 2010) as well as with regulators of the actin cytoskeleton (e.g. iso 1 Cdc42, N-WASP). Recent evidence from intersectin 1 knockout mice as well as acute perturbation studies using the calyx of Held as model system show that intersectin 1 is required for the rapid replenishment of fast-releasing SVs via a mechanism that involves its ability to associate with Cdc42 and dynamin (Sakaba et al., 2013). These results have led to the hypothesis that intersectin and, by extension, other endocytic factors located at the periphery of the AZ (Fig. 2B) may facilitate the clearance of AZ release sites from previously exocytosed material (Kawasaki et al., 2000) like for instance assembled SNARE complexes (Haucke et al., 2011, Hosoi et al., 2009). Consistent with this hypothesis, it has been shown that hair cell-specific disruption of AP-2 results in severe hearing defects due to rapid depression of inner hair cell exocytosis caused by impaired vesicle reloading of synaptic release sites and missorting of the Ca2+ sensor otoferlin, while endocytic retrieval of SV membranes proceeded nearly unperturbed (Jung et al., 2015). Although additional studies are required to dissect these complex phenotypes, these observations are consistent with a role for endocytic proteins in facilitating the removal of previously exocytosed material from release sites. Whether and how such release site clearance relates to the recently described ultrafast mode of endocytosis observed at optogenetically stimulated synapses (Watanabe et al., 2013) is an interesting question for future studies. A simple idea might be that curvature-sensing proteins such as endophilin, which are either present on SVs (Bai et al., 2010) or stored at AZ release sites, possibly in conjunction with tension-sensing proteins of unknown identity (Fig. 2C) and with F-actin, drive a rapid form of endocytosis whose main purpose is the restoration of AZ release sites.
    Open questions and perspectives In spite of accumulating evidence for the close coupling of SV exocytosis and endocytosis at different levels many questions remain unanswered (Table 1). For example, with current methodology at hand it remains difficult to discern defects in SV docking or priming of RRP vesicles during rapid high-frequency firing from impaired clearance of previously exocytosed material from release sites (Hosoi et al., 2009). The fact that genetic ablation of endocytic proteins such as the clathrin adaptor AP-2 (Jung et al., 2015) or intersectin 1 (Sakaba et al., 2013) impairs replenishment of rapidly releasable SVs on a subsecond timescale, has been interpreted in favor of their role in removal of exocytosed material from release sites. However, it cannot be ruled out that short-term depression due to delayed replenishment of fast releasing SVs is an indirect consequence of downstream defects caused by the missorting of SV-associated docking or priming factors such as otoferlin in inner hair cells (Jung et al., 2015). Equally important is the question how newly exocytosed SV proteins are prevented from diffusing into the axon (Gimber et al., 2015). Neither the nature of the presumed diffusion barrier, nor its relationship to the architecture of the presynapse including the AZ are known. Further technological advances, particularly in imaging SV exo-endocytosis at high spatial and temporal resolution paired with novel labeling strategies and genome-engineering may pave the way to addressing these important and exciting questions. Similarly, new tools and sensors are needed to explore the possibility that synapses may be able to sense and control lateral membrane tension, which may underlie the homeostatic control of SV exo- and endocytosis and/or enable rapid modes of SV retrieval.