MECHANISMS OF HORMONE AND TRANSMITTER SECRETION

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Our work continues to focus on the processes leading to fusion between granule and plasma membranes during exocytotic secretion from cells, including chromaffin cells, beta cells from Islets of Langerhans, nerve terminals, and mucin secreting cells from tissues affected by cystic fibrosis. The contact and fusion processes during secretion may be mediated by the calcium binding protein synexin (annexin VII). We have learned that Annexin VII is immunolocalized to formed elements in the cytoplasm of chromaffin cells, including the chromaffin granule membranes. Annexins, I, II and V can also be detected in these and other cells, but their distribution if different from that of synexin. Potassium channels have also been shown to occur on chromaffin granule membranes, although they are not sensitive to calcium. The role of these channels may be to rearrange [K] in recycling granules following exocytosis. In pituitary gonadotophs the potassium channels controlling the membrane potential are apamine sensitive, and regulate oscillations in membrane potential and internal calcium concentration. The mechanism of oscillation of calcium within these cells depends upon IP3 metabolism. In islets of Langerhans, glucose has a complex effect on intracellular calcium and secretion. The steady state effect of glucose is to induce rhythmic oscillations in intracellular calcium and electrical potential, but the earliest action of glucose is to lower the calcium ion concentration. A transgenic mouse with yeast hexokinase in the insulin secretion, which is lacking in neonatal islets, but is induced by exposure of the islets of prolactin. We have also developed a potential drug for cystic fibrosis based on our observation that the A1-receptor antagonist, 8-cyclopentyl-1,3-dipropyl xanthine activates chloride efflux from human epithelial and mouse fibroblast cell lines bearing the CFTR (delta F508) mutation but not the wild type CFTR. We have also learned that the Alzheimer's disease amyloid forms ion channels in bilayer membranes, and that this activity may be the basis of amyloid neurotoxicity in this disease.