Glucose-dependent regulation of gamma-aminobutyric acid (GABA A) receptor expression in mouse pancreatic islet alpha-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(A) receptor (GABA(A)R) antagonist SR95531 substantially reversed the inhibition of glucagon release by high glucose. GABA(A)R alpha4, beta3, and gamma2 subunit mRNAs were detected in mouse islets and clonal alphaTC1-9 cells, and immunocytochemistry confirmed the presence of GABA(A)Rs at the plasma membrane of primary alpha-cells. Glucose dose-dependently increased GABA(A)R expression in both islets and alphaTC1-9 cells such that mRNA levels at 16 mmol/l glucose were approximately 3.0-fold (alpha4), 2.0-fold (beta3), or 1.5-fold (gamma2) 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 Ca(2+) 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 Ca(2+) concentration, may modulate this response in the long term.
Bailey
Sarah J
SJ
Henry Wellcome Laboratories for Integrated Cell Signaling, and Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol, UK. s.bailey@bath.ac.uk
Ravier
Magalie A
MA
Rutter
Guy A
GA
D000818:Animals; D002118:Calcium / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology*; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000502:physiology*; D007328:Insulin / Q000502:physiology; D007515:Islets of Langerhans; D051379:Mice; D011188:Potassium / Q000494:pharmacology; D021122:Protein Subunits; D011724:Pyridazines / Q000494:pharmacology*; D012333:RNA, Messenger; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018756:GABA Antagonists; D007328:Insulin; D021122:Protein Subunits; D011724:Pyridazines; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D005934:Glucagon; C049853:gabazine; D005947:Glucose; D011188:Potassium; D002118:Calcium