MECHANISMS OF HORMONE AND TRANSMITTER SECRETION

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Our recent studies have focussed on the processes underlying granule assembly, synthesis and insertion of hormones into granules, movement of granules to sites of secretion and signals leading to membrane contact and fusion between granules and plasma membranes leading to exocytosis in chromaffin cells and Islets of Langerhans, our primary experimental systems. In the chromaffin cell a key element in assembly is the enzyme cytochrome b562, since it is the only "intrinsic membrane protein." We have cloned this protein and are now determining its primary structure. The function of this cytochrome may be to donate electrons to the intragranular enzyme DBH, so that it can convert dopamine to norepinephrine. The origin of the electrons is ascorbic acid. Movement to the site of membrane fusion may be regulated by actin filaments, since dissolution of these filaments potentiates secretion. Secretion signals may include protein kinase C substrates and IP3, as well as calcium. We have purified protein kinase C to homogeneity and are studying its properties. The final event, membrane fusion, may be mediated by synexin, the receptors for which include acidic phospholipids and perhaps specific proteins. Protons may also facilitate synexin action. Secretion signals seem to originate on the plasma membrane, either due to binding to specific receptor or changes in electrical potential. In chromaffin cells nicotinic and muscarinic cholinergic receptors allow calcium to enter the cytosol, from either outside or inside the cell, respectively. In the B cell similar muscarinic receptors mediate secretion, but the site of glucose action remains unresolved. However, both types of secretagogues cause cyclic changes in activity of K+ and Ca++ channels on the plasma membrane, resulting in cyclic changes in the rate of insulin secretion over time. Cyclic nucleotides also regulate coupling and secretory efficiency of B cells. The cytosolic pH may also regulate ionic channel function and secretion, but the latter two processes are not absolutely coupled.