Grant: Operating Grant

In insulin-secreting pancreatic islet beta-cells, membrane excitability which controls calcium influx required to cause exocytosis of insulin secretory granules, is regulated by two K+ channels, ATP-sensitive K+ (KATP) channels (sulfonylurea receptor 1-SUR1/Kir6.2 subunits) and voltage-gated K+ (Kv2.1) channels. Current treatment for diabetes with sulfonylureas is unsatisfactory since these drugs act on islet beta-cell SUR1 receptors to stimulate insulin secretion in a manner independent of glucose levels, which can cause hypoglycemia. More appropriate strategies would be to close the KATP channel in a glucose (or ATP)-dependent manner or to delay the closure of Kv2.1 channels, the latter prolonging glucose-evoked membrane depolarization, resulting in more sustained insulin secretion. We found that a class of proteins called SNAREs, originally shown to mediate exocytosis, directly bind and inhibit both KATP (at SUR1) and Kv2.1 channels. We will now examine the finest aspects of the structure-functional interactions between SNARE proteins and these K+ channels in absolute detail using a battery of state-of-the-art biophysical and imaging methodologies. We also propose that some of these interactions could actually influence exocytosis per se independently of ion channel regulation. This research into the novel SNARE-K+ channel interaction sites could reveal novel therapeutic targets to treat diseases of secretory deficiency (diabetes) or excels (hypersecreting endocrine tumors).