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  • Not only has the cortical actin

    2022-01-15

    Not only has the cortical Tenatoprazole network been found to influence plasma membrane properties but also to interact with exo- and endocytic vesicles (Gormal et al., 2015, Tomatis et al., 2013). The interplay between actin and membranes is integrally regulated by the phosphoinositide composition of the plasma membrane (Yin and Janmey, 2003). The plasma membrane concentration of Phosphatidylinositol (4,5)bisphosphate (PtdIns(4,5)P2) which is controlled by a number of effector proteins such as N-WASP and Arp2/3 (Gasman et al., 2004) regulates actin polymerization and establish linkages between the membrane and the actin cytoskeleton. In addition to classical biochemical and amperometric approaches, a number of technological advances such as improved fluorescent actin probes, new quantitative- and super resolution microscopy methods have provided new insight into how actomyosin mechanics control regulated exocytosis. The cortical actin network has been found to modify physical parameters of the plasma membrane such as tension, curvature and the diffusion of proteins and lipids. Furthermore, it restricts and directs secretory vesicle movement and also directly interacts with fusion and fission pores, as well as nascent bulk endosomes controlling their size and duration (Avraham et al., 1995, Tomatis et al., 2013, Eichler et al., 2006, Neco et al., 2004, Flores et al., 2014, MarĂ­a Cabeza et al., 2010). Intriguingly, F-actin's ability to actively move, shape and modify membranes make it an important modulator of fusion and fission properties. In nerve terminals, F-actin plays roles in synaptic vesicle mobilization, axonal vesicle trafficking and synaptic plasticity(Cingolani and Goda, 2008, Wolf et al., 2015) and endocytosis (Wu et al., 2016). High amounts of actin are found in synapses and dendritic spines were it is crucial for synapse function (Rust and Maritzen, 2015), the latter being formed by dendritic filopodia outgrowth (Fifkova, 1985, Landis et al., 1988, Matus et al., 1982)- an F-actin and myosin X dependent process(Kerber and Cheney, 2011, Plantman et al., 2013). In addition in central synapses neurotransmitter release at is regulated by F-actin (Morales et al., 2000).
    The actomyosin cortex actively modulates plasma membrane properties
    The cortical actin network in exocytosis The classical view of the cortical actin network in neurosecretory cells has been that of a physical barrier that prevents access of secretory vesicles to the plasma membrane in the resting state. Upon stimulation, this network has been shown to partly depolymerize (Cheek and Burgoyne, 1986, Perrin and Aunis, 1985) in a Ca- and scinderins-dependent manner (Rodriguez Del Castillo et al., 1990, Trifaro, 1999). Over time this picture has become more complex and dynamic (Fig. 1), with evidence that the cortical actin network is involved in (i) tethering secretory vesicles (Aschenbrenner et al., 2003, Au et al., 2007, Chibalina et al., 2007, Desnos et al., 2007, Huet et al., 2012, Tomatis et al., 2013), (ii) providing a platform for directed movement toward the plasma membrane (Papadopulos et al., 2015) and (iii) facilitating the generation of new release sites (de Paiva et al., 1999, Papadopulos et al., 2013a, Papadopulos et al., 2013b, Zakharenko et al., 1999).
    Future directions Future work could be directed at deciphering the precise interplay between actin and membrane organization, i.e. how activity-dependent actin reorganization affects membrane compartmentalization and membrane tension. Further studies are warranted to measure the exact changes in membrane tension upon stimulation in vivo and to decipher the role of this change in tension in the context of SNARE-mediated fusion. The advent of single molecule and high speed microscopy methods may help to decipher exact changes in the actin network in relation to vesicles with nanometre precision (Bademosi et al., 2017, Joensuu et al., 2016, Kasula et al., 2016). Especially, the temporal interplay between myosin II, dynamin, PtdIns(4,5)P2 and Arp2/3 seems a logical target for an in-depth analysis. High sensitivity FRET and correlation measurements (Zhao et al., 2013) in combination with electrophysiological measurements could help address these critical questions. To this day actin has been implicated in various overlapping roles in the processes leading to docking and fusion, such as: acting as barrier separating secretory vesicles from the plasma membrane, tethering secretory vesicles, directing secretory vesicles to docking and fusion sites, regulating the fusion pore dynamics and fusion profiles. Whether and how these different processes are linked and whether actin reorganization and fusion pore formation are activated by the same trigger remain open questions. The combination of actin and membrane tension measurements (Bretou et al., 2014) in combination with PIP2 modulators could reveal how force is transferred from the cortex to the plasma membrane to regulate the fusion process. Membrane tension measurements in the presence of actin effectors already point to new role for actin in exocytosis by controlling fusion profiles through plasma membrane tension (Wen et al., 2016).