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

Henry Wellcome Laboratories for Integrated Cell Signalling and Department of Biochemistry, School of Medical Sciences, University of Bristol, U.K. The current affiliation for S.J.B. is the Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, U.K. The current affiliation for G.A.R. is the Department of Cell Biology, Division of Medicine, Faculty of Medicine, Imperial College, Sir London, U.K

Address correspondence and reprint requests to Professor Guy A. Rutter, Department of Cell Biology, Division of Medicine, Faculty of Medicine, Imperial College, Sir Alexander Fleming Building, Exhibition Road, London SW7 2AZ, U.K. E-mail: g.rutter{at}imperial.ac.uk. Or to Dr. Sarah Bailey, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, U.K. E-mail: s.bailey{at}bath.ac.uk

Abbreviations: CREB, cAMP response element binding protein; GABA, -aminobutyric acid; GABA_AR, GABA_A receptor; PPG, preproglucagon; mRFP, monomeric red fluorescent protein

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, -aminobutyric acid (GABA) inhibited glucagon release to a similar extent (46%) as 10 mmol/l glucose (55%), and the selective GABA_A receptor (GABA_AR) antagonist SR95531 substantially reversed the inhibition of glucagon release by high glucose. GABA_AR 4, ß3, and 2 subunit mRNAs were detected in mouse islets and clonal TC1-9 cells, and immunocytochemistry confirmed the presence of GABA_ARs at the plasma membrane of primary -cells. Glucose dose-dependently increased GABA_AR expression in both islets and TC1-9 cells such that mRNA levels at 16 mmol/l glucose were 3.0-fold (4), 2.0-fold (ß3), or 1.5-fold (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 ß-cells contributes substantially to the acute inhibition of glucagon secretion from mouse islets by glucose and 2) that changes in GABA_AR expression, mediated by changes in intracellular free Ca²⁺ concentration, may modulate this response in the long term.

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