Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels

  title={Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels},
  author={Patrik Rorsman and P O Berggren and Krister B. Bokvist and Hans Ericson and Hanns Möhler and Claes-G{\"o}ran {\"O}stenson and Paul A. Smith},
THE endocrine part of the pancreas plays a central role in blood-glucose regulation. It is well established that an elevation of glucose concentration reduces secretion of the hyperglycaemia-associated hormone glucagon from pancreatic α2 cells. The mechanisms involved, however, remain unknown. Electrophysio-logical studies have demonstrated that α2 cells generate Ca2+-dependent action potentials. The frequency of these action poten-tials, which increases under conditions that stimulate glucagon… 
Glutamate is a positive autocrine signal for glucagon release.
Glucose Suppression of Glucagon Secretion
The data suggest that suppression occurs downstream from α-cell calcium signaling, presumably at the level of vesicle trafficking or exocytotic machinery, and supports the paracrine inhibition model.
Regulation of glucagon secretion at low glucose concentrations: evidence for adenosine triphosphate-sensitive potassium channel involvement.
The results indicate that loss of alpha-cell K(ATP) channels uncouples glucagon release from inhibition by beta-cells and reveals a role for K(ATOR) channels in the regulation of glucagonRelease by low glucose.
Glucose regulation of glucagon secretion.
Regulation of glucagon secretion by glucose: paracrine, intrinsic or both?
It is demonstrated that glucagon secretion measured in islets isolated from donors with type‐2 diabetes is reduced at low glucose and that glucose stimulates rather than inhibits secretion in these islets, and a unifying model is proposed that incorporates both modes of control.
Physiology of the pancreatic alpha-cell and glucagon secretion: role in glucose homeostasis and diabetes.
A focus in this review has been the multiple control levels that modulate glucagon secretion from glucose and nutrients to paracrine and neural inputs and the glucagon actions on glycaemia and energy metabolism.
A KATP Channel-Dependent Pathway within α Cells Regulates Glucagon Release from Both Rodent and Human Islets of Langerhans
It is proposed that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion within intact rodent and human islets.
γ-Hydroxybutyrate does not mediate glucose inhibition of glucagon secretion
It is found that GHB (4–10 μm) lacked effects on the cytoplasmic concentrations of the secretion-regulating messengers Ca2+ and cAMP in mouse α-cells and does not mediate the inhibitory effect of glucose on glucagon secretion.


Effect of Muscimol on Glucose-stimulated Somatostatin and Insulin Release from the Isolated, Perfused Rat Pancreas
It is suggested that GABA is potentially a modulator of islet somatostatin but not insulin release, and the fact that somatstatin, an inhibitor of insulin, can be suppressed 38% without coincidental increase in insulin release seems to indicate that, under high glucose conditions, som atostatin is without a significant paracrine effect on the beta-cellS.
gamma-Aminobutyric acid receptor channels in adrenal chromaffin cells: a patch-clamp study.
  • J. Bormann, D. Clapham
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1985
GABA-induced currents are potentiated by diazepam, indicating that anxiolytic drugs like the benzodiazepines might be involved in the regulation of anxiety states in the peripheral nervous system.
Voltage-activated currents in guinea pig pancreatic alpha 2 cells. Evidence for Ca2+-dependent action potentials
Membrane potential measurements demonstrated that both the Ca2+ and Na+ currents contribute to the generation of the action potential, and it is suggested that this behavior reflects the participation of a low-threshold Ca2- conductance in the pacemaking of alpha 2 cells.
Minimal Increases in Glucagon Levels Enhance Glucose Production in Man with Partial Hypoinsulinemia
It is concluded that, in man moderately deprived of insulin, even a marginal change in glucagon level induces a long-lasting hyperglycemia.
High concentration of GABA and high glutamate decarboxylase activity in rat pancreatic islets and human insulinoma.
The concentration of gamma-aminobutyric acid (GABA) and the activity of glutamate decarboxylase (GAD) in rat and human pancreas were measured by sensitive assay methods. The GABA concentration in rat
A patch clamp study of γ‐aminobutryic acid (GABA)‐induced macroscopic currents in rat melanotrophs in cell culture
The macroscopic currents induced in cultured rat melanotrophs by exogenous γ‐aminobutyric acid (GABA) were analysed using the patch clamp recording technique and suggested that the binding of 2 molecules of GABA to the receptor is required for the activation of the chloride channel.
Co-localization of GABAA receptors and benzodiazepine receptors in the brain shown by monoclonal antibodies
Because the monoclonal antibodies cross-react with human brain, they provide a means for elucidating those CNS disorders which may be linked to a dysfunction of a GABAA receptor, and two constituent proteins were identified immunologically.