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  • The first phase of insulin


    The first phase of insulin secretion is due to calcium signaling because of glucose sensing, increased cytoplasmic ATP levels, cellular depolarization, calcium influx and activation of calcium sensing molecules that eventually causes the fusion of the insulin granules to plasma membrane (exocytosis). In contrast, recruitment, traffic and UNC 0646 of the storage pool of the insulin secretory granules that are waiting for the cues in the standby condition is required for the second phase (Cui et al., 2011). However, there are other suggested mechanisms involving in inducing both phases of insulin secretion upon increasing glucose concentration (e.g. after meal), such as increasing cytosolic ATP, cAMP in addition to the cytoplasmic Ca2+ level (Kasai et al., 2014; Komatsu et al., 2013; Weiss et al., 2014).
    Distinct forms of exocytosis Various forms of exocytosis are observed in different cell types, which are depicted in Fig. 6 (Fig. 6A and B). During exocytosis, the content of the secretory granules may completely discharged through either complete fusion of the two membranes or formation of an expanding pore, which may occur with or without priming and docking (Rutter and Hill, 2006). The first phase of insulin secretion has linked to insulin vesicles docked to the plasma membrane in certain studies, whereas other conflicting data suggest the crash fusion (without apparent docking) as the underlying mechanism of exocytosis for the first phase of insulin release (Kasai et al., 2014). In the other form of fusion, referred as kiss-and-run fusion, a transient pore is in the granule, partially releases the contents, thus the vesicle may undergo another course of exocytosis (Rutter and Hill, 2006; MacDonald et al., 2006; Hou et al., 2009). A subset of kiss-and-run fusion may provide selective release of the vesicle components, termed as cavicapture (Hanna et al., 2009). The diameter of the fusion pore is approximately 0.3–2 nm (Kasai et al., 2014), even though the diameter of fusion pore of LDCVs is in the range of less than 1.4 to 5–10 nm (Hou et al., 2009). The different gate size, connecting the vesicle lumen and extracellular fluid, may prohibit passage of larger molecules such as 36 kDa insulin hexamers or even 6 kDa insulin monomers, whereas authorizes selective release of smaller components, such as ATP, Zn2+ and GABA (Hou et al., 2009) (Fig. 7). It has been demonstrated that the insulin granules predominantly undergo full fusion exocytosis, but less commonly may do kiss-and-run exocytosis (reported from 6% (Kasai et al., 2014) to 20% [52]) and sequential exocytosis (2%) (Kasai et al., 2014). Multi-vesicular or multi-granular is a quick and compound form of exocytosis, characterized by joining of multiple vesicles in the cytoplasm before fusing with the plasma membrane, which is frequently observed in hematopoietic cells (such as eosinophils, basophils and mast cells) (Kasai et al., 2014) (Fig. 6A and B). Sequential or compound exocytosis also has been reported in β cells, particularly during robust insulin release induction. Collectively, it is proposed that sequential exocytosis in β cells is repressed to prevent sugar crash arising from excessive and sudden insulin secretion (Kasai et al., 2014).
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    Introduction Transient receptor potential mucolipin 1 (TRPML1) is a nonselective Ca2+-permeable cation channel that is mainly expressed in late endosomal/lysosomal membranes, and is involved in the regulation of lysosomal pH and Ca2+ mobilization from lysosomes [1]. Loss-of-function mutations in TRPML1 causes the lysosomal storage disease, mucolipidosis type IV (MLIV) [2] and cells obtained from MLIV patients show lysosomal enlargement due to the accumulation of undigested materials, including lipids, polysaccharides, and proteins [3], leading to lysosomal dysfunction and cell death. In addition to digestion of cellular materials, lysosomes play crucial roles as a hub for both inward and outward membrane trafficking [4]. Notably, trafficking of lysosomes to and fusion with the plasma membrane, also known as lysosomal exocytosis, mediate various cellular responses, including plasma membrane repair [5], neurite outgrowth [6], and release of lysosomal content [7].