How Kiss-and-Run Can Make Us Sick: SOX4 Puts a Break on the Pore.

Abstract

Insulin is released by regulated exocytosis of secretory granules. At the heart of this process is a tight complex of three SNARE proteins (SNAP25 and syntaxin in the plasma membrane and synaptobrevin in the vesicle membrane) that forms during exocytosis (1). The complex pulls the two opposing membranes close enough to enable formation of a narrow fusion pore (∼1.5 nm), a proteolipidic structure that behaves somewhat similar to an ion channel (2). Owing to its small size, the pore essentially acts as a molecular sieve that allows passage of small molecules but prevents release of the larger peptide hormones (3,4) (Fig. 1 A ). Once formed, the fusion pore can then either expand irreversibly (“full fusion,” required for insulin secretion) or revert to the closed state (“kiss-and-run”) (5). The sieve effect is of particular interest in β-cells as insulin granules contain many peptides, nucleotides, and amino acids that are cosecreted with insulin and have their own signaling functions (6). Purines, in particular ATP, stimulate both insulin secretion and β-cell survival via P2X and P2Y receptors (7), and the resulting autocrine and paracrine feedback may be involved in synchronizing pulsatile insulin release (8). Glutamate stimulates and GABA inhibits glucagon release …