Study on multimolecular modulations of ATP-sensitive K^+ channels in pancreatic β-cells and their disharmony in diabetes.

点击翻译按钮获取中文摘要

ATP-sensitive K^+ (KATP) channels, composed of heteromultimers of sulfonylurea-receptor unit and a pore unit of inwardly rectifying K^+ channels, were studied with respect to effects of intracellular Ca^<2+> activity of the channels. It was found that elevation of intracellular Ca^<2+> conferred inhibition of functional transduction between binding of sulfonylureas to their receptors and closure of channels. Exposure of membrane patches to PIP_2 increased activity of KATP channels in association with reduction of ATP sensitivity of the channels. When measured membrane PIP_2 concentration by means of GFP (green fluorescent protein) labeled PH-domain contained probe, membrane fraction of GFP intensity decreased on exposure of β-cells to acetylcholine. The ATP sensitivity of the channel recorded in the presence of acetylcholine in the pipette in inside-out mode was increased as compared to that in control pipette solution. Acetylcholine, when it was applied to β-cell during cell-attached patch experiments, induced action currents. In whole-cell current recorded by nystatin-perforated mode, acetylcholine decreased the KATP channel currents at the glucose concentration of 2.8 mM. From these results, it is suggested that receptor-stimulation of pancreatic β-cells produces reduction of activity of the KATP channels associated with depolarization of membrane and an increase in output of insulin secretion around threshold concentrations of glucose. It is needed to further explore whether β-cells from diabetic animals have the inability of acetylcholine to depolarize the membrane and resultant perturbation of insulin secretion during parasympathetic neural stimulation.