DESCRIPTION: The posterior pituitary is formed by nerve terminals emanating from the hypothalamus. The posterior pituitary releases two peptide hormones, vasopressin, which regulates blood circulation and renal function, and oxytocin, which regulates various reproductive functions. The nerve terminals of the posterior pituitary are unusually large, making them ideal for experimentation with patch clamp and imaging techniques. This provides a unique opportunity to investigate basic mechanisms underlying the regulation of neurosecretion. The present plan continues an investigation of membrane excitability in the posterior pituitary, emphasizing two recently discovered aspects of ion channel modulation. The first of these involves the labile gaseous signaling molecule nitric oxide (NO), which modulates ion channels in the posterior pituitary. Experiments will explore how NO and the NO signaling cascade modulate ion channels. The second involves sigma receptors, which modulate posterior pituitary ion channels in response to a number of ligands, including antipsychotic and psychotomimetic drugs. NO and sigma receptors employ novel mechanisms in the modulation of ion channels, and represent important additions to the repertoire of signaling pathways that affect electrical excitability. These mechanisms of ion channel modulation take on added significance in the context of the posterior pituitary, because they contribute to the regulation of neurosecretion. This study will examine how alterations in channel function influence action potential shape, calcium entry, and the propagation of electrical impulses through the complex terminal arborizations of the posterior pituitary. These factors influence release in profoundly different ways. Thus, this project will test basic hypotheses about how chemical signaling controls neurosecretion. Since axons generally extend over considerable distances, exhibit complex geometries, and have very large numbers of secretory specializations, these studies of the relationship between axonal geometry and ion channel modulation will have broad implications for the role of axon terminals in neural circuit function.