GAMMA-AMINOBUTYRIC-ACID SECRETION FROM PANCREATIC NEUROENDOCRINE CELLS

Background & Aims: Neuroendocrine cells and tumors derived therefrom c ontain hormone-storing large dense core vesicles and neuron-like small synaptic vesicle analogues with unknown function. The aim of this stu dy was to characterize the small synaptic vesicle pathway in detail. M ethods: In human pancreatic neuroendocrine tumors and corresponding ma mmalian cell lines, the expression of key proteins of regulated secret ion were detected by immunofluorescence microscopy. Using H-3-gamma-am inobutyric acid (GABA), uptake and release by small synaptic vesicle a nalogues were studied. Results: Tumor tissues obtained from 14 patient s expressed key proteins of neurosecretion such as synaptobrevin, synt axins, and SNAP 25. These proteins were also found in the cell lines A R42J, BON, RIN, and INR. The cell lines specifically transported GABA by a low-affinity plasma membrane transporter and showed an adenosine triphosphate-sensitive GABA uptake into an intracellular compartment. Stored GABA was released upon stimulation by regulated exocytosis. Ele ctrophysiological analyses suggested that calcium-dependent secretion was mediated by activation of voltage-dependent calcium channels of ma inly the L type, but also of the N and probably the T type. Conclusion s: Small synaptic vesicle analogues in neuroendocrine cells and tumors can store and secrete GABA and probably other amino acid transmitters by regulated exocytosis comparable with neurons.