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, data 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 this protein is a target for the immunosuppressant drugs, cyclosporin and FK506, and that it is heterogeneously distributed within the nervous system and elsewhere. The annexin lipocortin I (annexin I) may be the mediator of barium activated secretion, and both synexin and lipocortin I activity appear to be modulated by nucleotides, including cAMP and ATP. Endonexin II (annexin V) has been shown to make up a substantial portion of the matrix vesicles used to create new bone, and to be the pathway for allowing calcium to be laid down at the appropriate site. Further studies on secretion of neurotransmitter have indicated that secretion can occur independently of extracellular calcium stores, and occurs at a much slower rate than conventional secretion. Pituitary gonadotrophs also secrete in response to a calcium signal, but in this case oscillations in membrane potential, run by an apamin-sensitive K+ channel cause oscillations in calcium concentration within the cells. MPTP, a neurotoxin which causes a Parkinsonian syndrome in man, also causes a similar syndrome in the goldfish, which like the human disease can de defended against with the MAO-B inhibitor L-deprenyl. The nucleotide binding fold portion of the CFTR has been expressed and shown to be a nucleotide-gated anion channel in planar lipid bilayers. Two A(1)- adenosine antagonists have been found to activate chloride efflux from cystic fibrosis cells, and DPCPX is being developed for a clinical trial. A macromolecular phospholipase-A inhibitor has been shown to inhibit mucin secretion from cystic fibrosis and control cells.