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Glucose-Dependent Regulation of γ-Aminobutyric Acid (GABAA) Receptor Expression in Mouse Pancreatic Islet α-Cells

The mechanism(s) by which glucose regulates glucagon secretion both acutely and in the longer term remain unclear. Added to isolated mouse islets in the presence of 0.5 mmol/l glucose, γ-aminobutyric acid (GABA) inhibited glucagon release to a similar extent (46%) as 10 mmol/l glucose (55%), and the selective GABAA receptor (GABAAR) antagonist SR95531 substantially reversed the inhibition of glucagon release by high glucose. GABAAR α4, β3, and γ2 subunit mRNAs were detected in mouse islets and clonal αTC1-9 cells, and immunocytochemistry confirmed the presence of GABAARs at the plasma membrane of primary α-cells. Glucose dose-dependently increased GABAAR expression in both islets and αTC1-9 cells such that mRNA levels at 16 mmol/l glucose were ∼3.0-fold (α4), 2.0-fold (β3), or 1.5-fold (γ2) higher than at basal glucose concentrations (2.5 or 1.0 mmol/l, respectively). These effects were mimicked by depolarizing concentrations of K+ and reversed by the L-type Ca2+ channel blocker nimodipine. We conclude that 1) release of GABA from neighboring β-cells contributes substantially to the acute inhibition of glucagon secretion from mouse islets by glucose and 2) that changes in GABAAR expression, mediated by changes in intracellular free Ca2+ concentration, may modulate this response in the long term.