Mechanisms of Exocytosis in Insulin‐Secreting B‐Cells and Glucagon‐Secreting A‐Cells

Abstract

In pancreatic B-and A-cells, metabolic stimuli regulate biochemical and electrical processes that culminate in Ca 2π -influx and release of insulin or glucagon, respectively. Like in other (neuro)endocrine cells, Ca 2π -influx triggers the rapid exocytosis of hormone-containing secretory granules. Only a small fraction of granules (Ͻ1% in insulin-secreting B-cells) can be released immediately, while the remainder requires translocation to the plasma membrane and further ''priming'' for release by several ATP-and Ca 2π -dependent reactions. Such functional organization may account for systemic features such as the biphasic time course of glucose-stimulated insulin secretion. Since this release pattern is altered in type-2 diabetes mellitus, it is conceivable that disturbances in the exocytotic machinery underlie the disease. Here I will review recent data from our laboratory relevant for the understanding of these processes in insulin-secreting B-cells and glucagon-secreting A-cells and for the identification of novel targets for antidiabetic drug action. Two aspects are discussed in detail: 1) The importance of a tight interaction between L-type Ca 2π -channels and the exocytotic machinery for efficient secretion; and 2) the role of intragranular acidification for the priming of secretory granules and its regulation by a granular 65-kDa sulfonylurea-binding protein.

Neurexin-1α Contributes to Insulin-containing Secretory Granule Docking

“…Granuphilin-mediated docking is inhibitory to insulin secretion (26,46,49). Although this finding is at odds with studies suggesting that docking precedes or facilitates insulin exocytosis (52,54,55), it is in line with a recent study showing attenuation of insulin secretion by ␣-synuclein, another ␤-cell protein that promotes secretory granule association with the membrane (56). By providing another example of a constituent of the docking apparatus that inhibits insulin secretion, our results support the idea that docking serves to constrain insulin exocytosis, halting secretory granules en route to SNARE complex formation and subsequent insulin release.…”

Regulation of two insulin granule populations within the reserve pool by distinct calcium sources

“…The fast-moving granules, shown in red, are the most acidic in the reserve pool. Since granule acidification has been shown as an important step during the preparation of granules for exocytosis (Barg, 2003;Hutton, 1989), our data show that the fast-moving population is well suited to becoming releasecompetent upon stimulation.…”

Beta cell chromogranin B is partially segregated in distinct granules and can be released separately from insulin in response to stimulation

“…Transport of proteins by endocrine cells is often envisaged as the flow of a mixture, transported from the endoplasmic reticulum to the Golgi complex and then to the SGs [37], which are finally exocytosed upon appropriate stimulation [38]. Previous studies had shown, however, that in various cell types the secretory proteins flowing out of the Golgi do not remain intermixed, but are sorted into different types of SGs [4-6, 39, 40].…”