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  • The exocytosis promotion is triggered

    2022-05-16

    The Nepicastat HCl promotion is triggered upon the binding of Ca2+ to the C2 domains of two Nepicastat HCl key protein groups, i.e. complexin and certain synaptogamins (Lai et al., 2017; Rizo and Xu, 2015). The first step of the vesicle fusion is the priming of the secretory vesicles, involved at the switching from close to open conformation of Habc domain in syntaxin. The Habc domain of syntaxin-1 at the N-terminus comprises three α-helices (Fig. 5). Prior to SNARE complex formation, the Habc domain of syntaxin is in close conformation bound to syntaxin-binding protein (Munc18-1) (Wang et al., 2017; Dawidowski and Cafiso, 2016). At the close state, Munc18-1 prevents syntaxin-1 to participate in SNARE complex formation, acting as a chaperon collapsing its Habc domain onto the Qa-SNARE domain (He et al., 2017). Another protein, named Munc13-1, plays a role in the conformational transition of syntaxin-1 to open state, cooperating with Munc18-1(Sec1/Munc18-1or SM proteins), Munc13-1, RIMs, Rab3A (Munc13-1–RIM-Rab3A tripartite complex), granuphilin, SNAPIN and tomosyn (Rizo and Rosenmund, 2008; Wang et al., 2017; Dawidowski and Cafiso, 2016). Tomosyn-1 is a SNAP25- and syntaxin-1-binding protein that contains a SNARE-like motif, which is expressed in the form of different isoforms in β cells. Although, tomosyn, SNAPIN or granuphilin may affect the insulin exocytosis, however their role in the whole process is likely putative and dispensable (Lai et al., 2017). Upon activation of SYTs, t-SNAREs on the cell membrane, including syntaxin (with Qa-SNARE domain) and SNAP25 (with Qb and Qc-SNARE domains) attract the vesicles with synaptobrevins/VAMPs as the v-SNARE (containing an R- SNARE domain) to establish a four-component bundle complex (a coiled-coil quaternary structure) (Rizo and Xu, 2015; Huang et al., 2018). The SNARE complex emerges from both the hydrophobic reactions of leucine zippers between the t- and v-SNAREs as well as the electrostatic dipole-dipole interactions between three glutamine residues from Qa-, Qb- and Qc-SNAREs with one arginine residue from the R-SNARE, termed as zero ionic layer. The resulting SNARE core complex pulls two membranes into close proximity, likely via zippering the SNAREs, that eventually leads to fusing of two membranes or forming a transient pore to allow for discharging the cargo (Rizo and Rosenmund, 2008; Rizo and Xu, 2015; Huang et al., 2018). The fusion starts by forming a fusion stalk, which is expanded to form a fusion pore (Fig. 7). Meanwhile, converting the SNARE complex from cis to trans conformation, causes latter expansion of the fusion pore (Huang et al., 2018). The complex assembly might provide the energy required for fusion. N-Ethylmaleimide-sensitive factor (NSF) is a homo-hexameric AAA ATPase that plays an important role in intracellular vesicle transport and exocytosis, disassembling SNARE complex via hydrolysis of ATP (Rizo and Xu, 2015; Huang et al., 2018; Bertram et al., 2018). Synucleins and cysteine string proteins (CSPs) facilitate priming and promote SNARE complex assembly, following of their chaperone activities (Huang et al., 2018).
    Oscillation and biphasic secretion of insulin Both in vitro and in vivo experiments demonstrated the pulsatile fashion of insulin secretion upon an increase in glucose concentration, which are a ubiquitous event among species despite slight differences (Song et al., 2000; Nunemaker and Satin, 2014). The findings denote a pulsatile release of insulin rather than a steady and continuous stream, which have been demonstrated for other types of endocrine systems (Álvarez de Toledo et al., 2018) Two distinct modes of postprandial insulin secretion have been identified, responding to the glucose stimulation or increases in cytoplasmic Ca2+ levels (Kasai et al., 2014). The biphasic term of insulin secretion is termed as the stimulated (postprandial) state and the basal (post-absorptive) state. The first phase of insulin secretion is immediately starts in response to increased glucose levels, ceasing within the first few minutes (Fu et al., 2013; Komatsu et al., 2013). The transient first phase is followed by the sustained second phase of insulin secretion. In the other word, the first phase of insulin release is a short-term and fast mode (lasting approximately 3–10 min), while the second phase of insulin secretion is slow and continued, which reaches a plateau within 1–3 h and lasts for longer period. In contrast to the first phase, the second phase of insulin secretion is independent of the extracellular glucose level (Kasai et al., 2014; Fu et al., 2013; Komatsu et al., 2013).