title: Gamma-aminobutyric acid up- and downregulates insulin secretion from beta cells in concert with changes in glucose concentration.
abstract: OBJECTIVE
  The role of gamma-aminobutyric acid (GABA) and A-type GABA receptors (GABA(A)Rs) in modulating islet endocrine function has been actively investigated since the identification of GABA and GABA(A)Rs in the pancreatic islets. However, the reported effects of GABA(A)R activation on insulin secretion from islet beta cells have been controversial.
  
  
  METHODS
  This study examined the hypothesis that the effect of GABA on beta cell insulin secretion is dependent on glucose concentration.
  
  
  RESULTS
  Perforated patch-clamp recordings in INS-1 cells demonstrated that GABA, at concentrations ranging from 1 to 1,000 micromol/l, induced a transmembrane current (I(GABA)) which was sensitive to the GABA(A)R antagonist bicuculline. The current-voltage relationship revealed that I(GABA) reversed at -42+/-2.2 mV, independently of glucose concentration. Nevertheless, the glucose concentration critically controlled the membrane potential (V (M)), i.e., at low glucose (0 or 2.8 mmol/l) the endogenous V (M) of INS-1 cells was below the I(GABA) reversal potential and at high glucose (16.7 or 28 mmol/l), the endogenous V (M) of INS-1 cells was above the I(GABA) reversal potential. Therefore, GABA dose-dependently induced membrane depolarisation at a low glucose concentration, but hyperpolarisation at a high glucose concentration. Consistent with electrophysiological findings, insulin secretion assays demonstrated that at 2.8 mmol/l glucose, GABA increased insulin secretion in a dose-dependent fashion (p<0.05, n=7). This enhancement was blocked by bicuculline (p<0.05, n=4). In contrast, in the presence of 28 mmol/l glucose, GABA suppressed the secretion of insulin (p<0.05, n=5).
  
  
  CONCLUSIONS
  These findings indicate that activation of GABA(A)Rs in beta cells regulates insulin secretion in concert with changes in glucose levels.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, ON, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Dong
authors.forename: M
authors.initials: M
authors.lastname: Kumar
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: A
authors.initials: A
authors.lastname: Gyulkhandanyan
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Xiang
authors.forename: B
authors.initials: B
authors.lastname: Ye
authors.forename: J
authors.initials: J
authors.lastname: Perrella
authors.forename: A
authors.initials: A
authors.lastname: Hyder
authors.forename: N
authors.initials: N
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Wheeler
authors.forename: W-Y
authors.initials: WY
authors.lastname: Lu
authors.forename: Q
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects*; D004594:Electrophysiology; D005786:Gene Expression Regulation; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D007328:Insulin; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D005947:Glucose; D002118:Calcium