Abstract
Pancreatic islet β-cells produce large amounts of γ-aminobutyric acid (GABA), which is co-released with insulin. GABA inhibits glucagon secretion by hyperpolarizing α-cells via type-A GABA receptors (GABAARs). We and others recently reported that islet β-cells also express GABAARs and that activation of GABAARs increases insulin release. Here we investigate the effects of insulin on the GABA-GABAAR system in the pancreatic INS-1 cells using perforated-patch recording. The results showed that GABA produces a rapid inward current and depolarizes INS-1 cells. However, pre-treatment of the cell with regular insulin (1 µM) suppressed the GABA-induced current (IGABA) by 43%. Zinc-free insulin also suppressed IGABA to the same extent of inhibition by regular insulin. The inhibition of IGABA occurs within 30 seconds after application of insulin. The insulin-induced inhibition of IGABA persisted in the presence of PI3-kinase inhibitor, but was abolished upon inhibition of ERK, indicating that insulin suppresses GABAARs through a mechanism that involves ERK activation. Radioimmunoassay revealed that the secretion of C-peptide was enhanced by GABA, which was blocked by pre-incubating the cells with picrotoxin (50 µM, p<0.01) and insulin (1 µM, p<0.01), respectively. Together, these data suggest that autocrine GABA, via activation of GABAARs, depolarizes the pancreatic β-cells and enhances insulin secretion. On the other hand, insulin down-regulates GABA-GABAAR signaling presenting a feedback mechanism for fine-tuning β-cell secretion.
Highlights
Gamma-aminobutyric acid (GABA) is a major neurotransmitter in the central nervous system (CNS), where GABA produces fast inhibition in mature neurons primarily by activation of Atype GABA receptor (GABAAR), a hetero-pentameric Clchannel [1]
These results suggest that GABA, via activation of GABAAR, induces membrane potential depolarization in pancreatic INS-1 cells
Pancreatic b-cells produce a large amount of GABA [27], whereas GABAARs are expressed in both b-cells [6,15] and a-cells [7,12]
Summary
Gamma-aminobutyric acid (GABA) is a major neurotransmitter in the central nervous system (CNS), where GABA produces fast inhibition in mature neurons primarily by activation of Atype GABA receptor (GABAAR), a hetero-pentameric Clchannel [1]. The GABAARmediated hyperpolarization of a-cells represents a physiological mechanism for glucose-induced suppression of glucagon release because blockade of GABAAR diminishes the inhibitory effect of high glucose on glucagon secretion in isolated rat [10] or mouse [11] islets. In relation to this notion, we have recently demonstrated that insulin suppresses glucagon secretion by enhancing intra-islet GABA-GABAAR signaling through translocation of GABAAR from an intracellular pool to the cell surface of a-cells [12]
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