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  • In addition the interplay of membrane


    In addition the interplay of membrane curvature induced tension at the fusion pore and Sodium 4-Aminosalicylate induced tension across the PM seems to be a worthwhile target for investigation. The roles of dynamin and myosin II and especially their spatial and temporal dynamics during activity warrant further research. Another interesting direction would be to investigate whether actin dependent plasma membrane subcompartmentalisation facilitates the pre-organization of nascent fusion sites and how activity allows for dynamic membrane reorganization, including SNARE and PIP2 clustering to facilitate docking and fusion.
    Conclusion In summary, there are a multitude of pathways in which membrane and actin interaction control regulated exocytosis. The structure of the cortical actin itself provides a base for other proteins to form a “membrane skeleton” (Fujiwara et al., 2016) that limits diffusion of proteins and lipids within the plasma membrane. Actin can drive the formation of filopodia and subsequent changes in cell surface morphology leading to the creation of new release sites (Papadopulos et al., 2013a, Papadopulos et al., 2013b). Actin modulators and phosphoinositide levels regulate polymerization and depolymerisation of the cortical actin which affects membrane tension and access of vesicles to the plasma membrane. Actin coats have been observed to stabilize and squeeze vesicles in some secretory systems. The actin effectors myosin II and dynamin have been shown to affect release kinetics. Finally, the cortical actin network is potentially involved in the organization of release sites through interactions with SNARE or raft proteins.
    Exocytosis and insulin release Over fifty years of study of pancreatic beta cells have led to a comprehensive understanding of how glucose initiates the signaling cascade that leads to insulin secretion [1], [2], [3], [4] (Fig. 1A). At a simplified level, when blood glucose is elevated, transporters move glucose into beta cells of the pancreatic islets. As these sugars are metabolized, the cytoplasmic ratio of ATP/ADP increases, closing ATP-sensitive potassium channels (K-ATP channels) and blocking potassium efflux from the cell [5]. The resulting depolarization of the cell’s plasma membrane opens voltage-gated calcium channels, allowing extracellular calcium to enter the cytoplasm (Fig. 1A). Like many regulated secretory systems, elevated intracellular calcium is the ultimate trigger for exocytosis, stimulating the fusion of insulin-containing dense-core granules with the plasma membrane and the release of their luminal contents into the blood [6]. With glucose stimulation, beta cells exhibit a biphasic pattern of insulin release composed of an intense and transient first phase followed by a second sustained phase that builds slowly over time [2], [5]. The pathway described above is active in both phases of biphasic secretion and oscillatory changes in calcium underlie the two-component behavior. In addition to electrogenic effects, glucose metabolism potentiates release in pathways that act downstream of calcium influx. Additionally, other pathways, such as receptor-mediated cAMP elevation contribute to the control of calcium signaling and may directly activate protein kinases [7]. These other pathways integrate extracellular signals from neurotransmitters or hormones and provide additional layers of control over insulin secretion often via cAMP-dependent pathways [7], [8]. In the end, all these signals funnel into the same conserved molecular machinery that drives the fusion of insulin-loaded granules with the plasma membrane. In beta cells the fusion of exocytotic vesicles is driven by a macromolecular complex composed of over a dozen proteins and lipids [6] (Fig. 1B). This machinery is broadly conserved in regulated exocytosis from yeast to humans and across diverse secretory systems that are found in endocrine, neuroendocrine, neuronal, cardiac, reproductive and other tissues. The core components are the SNARE proteins: syntaxin, SNAP25, and VAMP [6]. These three proteins are embedded in opposing vesicular (VAMP) and plasma membranes (syntaxin and SNAP25) and interact to form a four-helical bundle when secretory vesicles dock at the plasma membrane. When exocytosis is initiated, the helical bundle zippers completely, which produces mechanical force that pulls the two membranes into close apposition. In vitro, the SNAREs are sufficient to drive membrane fusion [9], [10]. However, in cells additional proteins control the distinct steps in a secretory vesicle’s lifecycle: (1) translocation to and docking with the plasma membrane, (2) priming that activates the vesicle to fuse, and (3) fusion pore formation (Fig. 1B). For example, secretory vesicles are coated in small Rab GTPases such as Rab27a and Rab3a, and their effectors, including rabphilin and granuphilin [11]. These proteins play key roles in vesicle trafficking and docking. Priming is believed to involve partial assembly of the SNARE proteins mediated by several modulators including munc13, munc18, CAPS, tomosyn and others [6]. Finally, membrane fusion needs the primary calcium sensor for exocytosis, synaptotagmin, a vesicular membrane protein, which binds calcium and helps to catalyze membrane fusion through still-controversial mechanisms [12], [13], [14]. Together these molecules compose the macromolecular assembly that mediates vesicle fusion in a carefully regulated manner. One pathway for regulation of this process is PKC [15].