MECHANISMS OF HORMONE AND TRANSMITTER SECRETION

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Regulation of secretory processes and the mechanisms of external activation and internal control by calcium continue to be the principal interests of the LCBG. In the classical chromaffin cell system we have found that the nicotinic receptor regulating secretion of chromaffin granule contents by exocytosis is itself controlled by sigma opiate receptors. Chromaffin granules contain dopamine monooxygenase (DBH) which is responsible for synthesis of noradrenaline. We found that external ATP regulates DBH function in chromaffin granules by a mechanism unrelated to effects of proton pumping. A major chromaffin granule membrane protein cytochrome b561 has been cloned and localized to human chromosome 17q11-qter. When the chromaffin cell is stimulated more granule contents are synthesized but cytochrome b561 levels maintained. The new vesicles apparently have greater secretory quanta. Islets of Langerhans secrete insulin in response to glucose and other stimuli. We found that both glucose- and muscarinic agonist-potentiated secretion is mediated by calcium from both intracellular and extracellular sources. Glucose sensing mechanisms in neonatal rat islets are non-functional, and are thought to model changes occurring during type II diabetes. However, glucose sensitivity can be prematurely induced by exposure of the islets to prolactin. Endothelial cells have been shown to form relatively impermeable sheets in culture, and to join together by lucifer yellow- delimited gap junctions. Albumin has a modulatory effect on endothelium permeability which is species specific. Ascorbic acid accumulation and recycling is enhanced in activated human neutrophils. In situ kinetics of ascorbate utilization can be used to evaluate true requirements for man. A toxic effect of ascorbate is the suppression of insulin secretion from isolated islets, and may be the basis for the tight control of blood levels in intact organisms. Calcium action during exocytotic control of blood levels in intact organisms. Calcium action during exocytotic membrane fusion may be controlled by synexin (annexin VII), and we have recently localized human synexin gene to chromosome 10q21.1-21.2. The structure of the gene varies from other members of the annexin gene family. In anticipation of studies with a synexin knockout mouse we have cloned synexin from mouse, and have characterized the mouse synexin genomic sequence. It is virtually identical to the human case. Calcium metabolism in muscle has also been studied with the local anesthetic tetracaine. Rynaodine receptors have also been characterized in lobster skeletal muscle. Finally, beta amyloid ion channels have been further characterized and evaluated as possible toxic agents in the genesis of Alzheimer's disease.