Mechanisms of exocytosis in insulin-secreting B-cells and glucagon-secreting A-cells.
In pancreatic B- and A-cells, metabolic stimuli regulate biochemical and electrical processes that culminate in Ca2+-influx and release of insulin or glucagon, respectively. Like in other (neuro)endocrine cells, Ca2+-influx triggers the rapid exocytosis of hormone-containing secretory granules. Only a small fraction of granules (<1% 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 Ca2+-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 Ca2+-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.
Barg
Sebastian
S
Department of Physiological Sciences, Molecular and Cellular Physiology, Lund University, Sölvegatan 19, BMC F11, S-221 84 Lund, Sweden. sebastian.barg@mphy.lu.se
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000502:physiology; D015220:Calcium Channels / Q000502:physiology; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D003594:Cytoplasmic Granules / Q000502:physiology; D005089:Exocytosis / Q000502:physiology*; D005934:Glucagon / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism / Q000502:physiology*; D007700:Kinetics; D013453:Sulfonylurea Compounds / Q000494:pharmacology
D015220:Calcium Channels; D018118:Chloride Channels; D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds; D000255:Adenosine Triphosphate; D005934:Glucagon; D002118:Calcium