Glucose Inhibition of Glucagon Secretion From Rat α-Cells Is Mediated by GABA Released From Neighboring β-Cells

Abstract

γ-Aminobutyric acid (GABA) has been proposed to function as a paracrine signaling molecule in islets of Langerhans. We have shown that rat β-cells release GABA by Ca²⁺-dependent exocytosis of synaptic-like microvesicles. Here we demonstrate that GABA thus released can diffuse over sufficient distances within the islet interstitium to activate GABA_A receptors in neighboring cells. Confocal immunocytochemistry revealed the presence of GABA_A receptors in glucagon-secreting α-cells but not in β- and δ-cells. RT-PCR analysis detected transcripts of α₁ and α₄ as well as β_1–3 GABA_A receptor subunits in purified α-cells but not in β-cells. In whole-cell voltage-clamp recordings, exogenous application of GABA activated Cl⁻ currents in α-cells. The GABA_A receptor antagonist SR95531 was used to investigate the effects of endogenous GABA (released from β-cells) on pancreatic islet hormone secretion. The antagonist increased glucagon secretion at 1 mmol/l glucose twofold and completely abolished the inhibitory action of 20 mmol/l glucose on glucagon release. Basal and glucose-stimulated secretion of insulin and somatostatin were unaffected by SR95531. The L-type Ca²⁺ channel blocker isradipine evoked a paradoxical stimulation of glucagon secretion. This effect was not observed in the presence of SR95531, and we therefore conclude that isradipine stimulates glucagon secretion by inhibition of GABA release.