A review on neurosecretory granules: their contents and mechanisms of release.

The available evidence suggests that hormones and neurophysins are associated exclusively with the neurosecretory granules, each of which contains approximately 6 times 10-4 molecules of each. Hormones and carrier proteins are complexed within the granules and the complexes are densely packed. The processes that keep the intragranular space in osmotic equilibrium with the axoplasm require further study. Freeze-fracture data, as well as studies in which histochemical methods for the detection of glycoproteins were used, suggest that the intragranular aspect of the granule membrane mostly resembles the extracellular half of the plasma membrane; on the other hand, the cytoplasmic aspects of plasma and granule membrane have similar characteristics, which may be important in permitting membrane fusion to take place prior to secretion. Little is known about the molecular species involved in this interaction between granule and plasma membrane, except that calcium is a cofactor in this process. Release is triggered in vivo by propagated action potentials which cause an influx of calcium into the secretory endings. Newly formed granules, and other granules located at the periphery of the endings are preferentially released. Irrespective of the type of stimulation of secretion, release involves the diffusion into the extracellular space of granule core constituents. The best evidence so far in support of this view comes from ultrastructural studies showing images of exocytosis, as well as from biochemical studies demonstrating that hormones and carrier proteins are secreted concomitantly in a great variety of experimental or clinical conditions, without an associated release of granule membrane constituents or of enzymes of cytoplasmic origin. Recovery mechanisms following secretion require new synthesis of granule constituents and restoration of the resting internal concentrations of potassium, sodium, and calcium. Membrane surface area is restored following exocytosis by compensatory endocytosis which involves indiscriminate uptake of extracellular medium into the secretory axon terminals. While much progress has been made in research on the cellular and subcellular processes that take place in neurons which produce, store, and secrete neurohypophyseal hormones and their carrier proteins, neurophysins, many pressing questions remain to be answered. New developments, such as organ culture of supraoptic nuclei94-96 and the recent isolation of a clone of mouse hypothalamic cells capable of synthesizing vasopressin and neurophysin,97 will hopefully allow some of these problems to be solved in the future.