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, gamma-aminobutyric acid (GABA) inhibited glucagon release to a similar extent (46%) as 10 mmol/l glucose (55%), and the selective GABA, receptor (GABA(A)R) antagonist SR95531 substantially reversed the inhibition of glucagon release by high glucose. GABA(A)R alpha 4, beta 3, and gamma 2 subunit mRNAs were detected in mouse islets and clonal alpha TC1-9 cells, and immunocytochemistry confirmed the presence of GAB(A)Rs at the plasma membrane of primary alpha-cells. Glucose dose-dependently increased GABAAR expression in both islets and aTC1-9 cells such that mRNA levels at 16 mmol/l glucose were similar to 3.0-fold (alpha 4), 2.0-fold (P3), or 1.5-fold (gamma 2) 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 beta-cells contributes substantially to the acute inhibition of glucagon secretion from mouse islets by glucose and 2) that changes in GABA(A)R expression, mediated by changes in intracellular free Ca2+ concentration, may modulate this response in the long term.