The main consequence of glucose catabolism is the elevation
The main consequence of glucose catabolism is the elevation of ATP concentration, which in turn suppresses the ATP sensitive potassium (KATP) channels gating function. The KATP channels are octamers composed of the tetrameric inward-rectifying potassium channels (with Kir6.1 and Kir6.2 subunits), that are joined to the tetrameric sulfonylurea receptor (SUR1) subunits. Once the intracellular ATP: ADP ratio is increased, the KATP channels are closed (Komatsu et al., 2013; Weiss et al., 2014). As a result, the K+ ions cannot leave the cell and the intracellular concentration of K+ is increased, leading to less negative charge inside the cell referred as depolarization (Kasai et al., 2014; Rutter and Hill, 2006; Xiong et al., 2017; Drews et al., 2010) (Fig. 4).
Closure of KATP channels causes depolarization in β cells, leading to calcium influx through L-type voltage gated calcium channels (L-VGCCs), particularly Ca v1.2. Elevation of cytoplasmic Ca2+ levels can trigger exocytosis. Ca2+ can also promote glucose catabolism, provoking pyruvate dehydrogenase (PDH) complex (Komatsu et al., 2013; Gauthier and Wollheim, 2008) (Fig. 4). Calcium ions can bind to the calcium-binding domains on various proteins, such as the EF-hand domain of apo-calmodulin or C2 domain of synaptogamins (SYTs), complexin and certain classes of phospholipase-A (PLA) and adenylyl cyclase (ACs). However, not all of the C2 domains containing proteins are capable for binding to Ca2+ ions (Lai et al., 2017). Binding to Ca2+ can stimulate calcium sensors and enzymes that in turn leads to trigger various signaling cascade and insulin release through exocytosis (Fig. 4) (Lai et al., 2017).
Exocytosis of the secretory vesicles In the context of exocytosis, the vesicle-mediated release, neurotransmission at the synaptic vesicles and traffic of the membrane components from internal source follows the similar mechanism and rules, which may differ in certain components. There is no consensus on certain molecular participants in the insulin secretory vesicle exocytosis in particular. (Rizo and Rosenmund, 2008; Rizo and Xu, 2015; Südhof, 2013; Huang et al., 2018). Synaptogamins (also known as synaptotagmins) have two calcium Talabostat mesylate termed as C2 domains A and B (C2A and C2B) at C-terminal (Fig. 4). Certain types of SYTs function as calcium sensors, and bind to Ca2+ through their homologues C2 domains (Fu et al., 2013; McCulloch et al., 2011; Huang et al., 2018). However, some of them such as SYT4 and SYT8 are not able to bind to Ca2+. Although there are various types of SYTs in different species and insulin-secreting cell lines, even though the expression and involvement in insulin secretion of certain SYT types in naive β cells is still controversial (Drews et al., 2010; Lai et al., 2017; Rizo and Xu, 2015; Südhof, 2013; Ma et al., 2011). There are several proteins located on the surfaces of both vesicles and the targets (plasma membrane), which are responsible for buckling the two membranes destined to fuse into close proximity. The superficial proteins are termed as SNARE (SNAP receptor) proteins, since they possess α-helical domains named as SNARE motifs that have a high tendency to form coiled coils with each other. Two major types of SNARE proteins are located on the surface of vesicles (v-SNAREs) and the target (t-SNAREs) membranes, which mediate vesicle fusion through forming core- or trans-SNARE complex (Drews et al., 2010). The SNARE motifs are classifying as either Q-SNAREs for presence of glutamine (Q) or R-SNAREs for possessing an arginine (R) residue at a specific location within the protein sequence. There are two major types of t-SNAREs located on the plasma membrane, referred as syntaxin and synaptosomal nerve-associated protein 25 (SNAP-25) (Drews et al., 2010; Rizo and Xu, 2015). Syntaxin has a transmembrane domain at C-terminal portion, an SNARE domain called Qa- or H3-SNARE motif and an N-terminal regulatory domain, named as Habc domain. SNAP25 is a lipid-anchored protein that possesses two SNARE domains, named as Qb- and Qc-SNARE motifs in the N and C terminus, respectively (Rizo and Rosenmund, 2008; Rizo and Xu, 2015). The Qb- and Qc-SNARE domains are connected with a random coil linker region with cysteine residues covalently bound to palmitoyl side chains, through which SNARE is anchored to the inner-leaf of cell membrane (Fig. 4, Fig. 5) (Rizo and Rosenmund, 2008; Rizo and Xu, 2015). Palmitoylation of SNAP-25 provides plasticity for the SNARE core complex, allowing its dissociation during fusion. On the other side, synaptobrevins that are a part of vesicle-associated membrane protein (VAMP) family are located on the surface of vesicles. The v-SNAREs are small proteins with a transmembrane domain at C-terminal and the cytoplasmic domain, referred as R-SNARE motif (Rizo and Rosenmund, 2008; Rizo and Xu, 2015; Südhof, 2013).