EXPRESSION OF FUNCTIONAL GABA(A) RECEPTORS IN NEUROENDOCRINE GASTROPANCREATIC CELLS

Gastropancreatic neuroendocrine cells synthesize large amounts of gamma-aminobutyric acid (GABA). This amino acid neurotransmitter appears to be stored in and released from, vesicles similar to small synaptic vesicles. So far, the function of GABA in gastropancreatic, neuroendocrine cells has not been clarified. Previous work suggested that only pancreatic, glucagon-producing alpha(2) cells contain functional GABA(4) receptors. Using subunit-specific antibodies in sections of human antral mucosa, a human gastrinoma and rat pancreas, we show that expression of GABA(4) receptors is abundant in gastropancreatic, neuroendocrine cells. Using the patch-clamp technique in the whole-cell mode we demonstrate that both the rat insulinoma cell line RIN 38 and the amphicrine cell line AR42J express functional GABAA receptors, which are characterized by a relatively low benzodiazepine and Zn2+ sensitivity and by an insensitivity to the inverse benzodiazepine agonist 6,7-alpha-methoxy-4-ethyl-beta-carboline-3-carboxyrate (DMCM). In contrast to neurons, activation of GABAA receptors leads to a membrane depolarization. This depolarization presumably activates voltage-gated Ca2+ channels, resulting in an increase in cytosolic Ca2+ concentration, [Ca2+](i), as shown with the fluorimetric dye fura-2. The combination of GABA release, GABA(4) receptor activation and the [Ca2+](i) increase could constitute an autocrine mechanism, modulating the release of hormones such as gastrin, insulin and somatostatin.