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FACTORS OF STRUCTURE AND FUNCTION COUPLING BETWEEN SUR/KIR6.2IN PANCREATIC B-CEELS

胰腺 B-CEELS 中 SUR/KIR6.2 结构和功能耦合的因素

基本信息

批准号：
10671080
负责人：
KAKEI Masafumi
金额：
$ 1.73万
依托单位：
KAGOSHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671080/
关键词：
K-ATP CHANNEL SULFONYLUREA INSULIN SECRETION PANCREATIC B-CELLS PIP2 SUR KIR Kir イオンチャネル糖尿病スルフォニル尿素薬 β細胞

项目摘要

ATP-sensitive KィイD1+ィエD1 channels play an important role in the glucose-stimulated insulin secretion in pancreatic β-cells. The channel determine the resting membrane potential of β-cells and closure of the channel is the first event appeared in glucose-stimulated β-cells. It has been established that sulfonylureas initiate the insulin secretion as a result of closure of the K-ATP channel by binding to their receptor. The channel is composed of sulfonylureas receptor, SUR, and inwardly rectifying channel, Kir6.2. We studied a mechanism underlying signal transduction from the SUR to Kir6.2 and following results were obtained.(1) Tolbutamde (SU) inhibited the ATP-sensitive KィイD1+ィエD1 channels. The sensitivity of the channel to tolburtamide was reduced after the treatment of the channel with 2 μM CaィイD12+ィエD1.(2) At this time, the increasing effect of ADP on the channel activity disappeared.(3) The sensitivity of the channel to ATP was kept normal.(4) PIP2, membrane phospholipid, prevented the loss of tolbutamide sensitivity induced by CaィイD12+ィエD1.(5) From these results, we suggest that CaィイD12+ィエD1 may influence the channel protein by decreasing the sensitivity to tolbutamide and ADP. PIP2 may be reduced by the treatment with high CaィイD12+ィエD1. These may interfarewith the signalling from SUR to Kir6.2 and PIP2 my be required for maintaining the signalling between both subunits.(6) It has been known that the channel similar to b-cell type K-ATP channel is expressed in the myocardial cells. When PIP2 was decerased by exposure of cells to extracellular ATP, the K-ATP channel current was decreased.

atp敏感的κ D1+ κ D1通道在胰腺β细胞中葡萄糖刺激的胰岛素分泌中起重要作用。通道决定了β-细胞的静息膜电位，通道的关闭是葡萄糖刺激β-细胞出现的第一个事件。已经确定，磺脲类药物通过与其受体结合而关闭K-ATP通道，从而启动胰岛素分泌。该通道由磺脲类受体SUR和内整流通道Kir6.2组成。我们研究了从SUR到Kir6.2的信号转导机制，得到了以下结果。(1) tolbuamde （SU）抑制atp敏感的K γ γ γ + γ γ γ通道。用2 μM Ca γ γ γ + γ γ γ γ + γ γ γ处理后，通道对托尔伯胺的敏感性降低。(2)此时ADP对通道活性的增加作用消失。(3)通道对ATP的敏感性保持正常。(4)膜磷脂PIP2可阻止Ca γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ γ。(5)从这些结果，我们认为Ca γ γ γ可能通过降低对甲苯丁胺和ADP的敏感性来影响通道蛋白。高钙D12+钙D1处理可降低PIP2水平。这些可能干扰从SUR到Kir6.2和PIP2的信号传递，这是维持两个亚基之间信号传递所必需的。(6)已知心肌细胞中存在类似于b细胞型K-ATP通道的表达。当细胞暴露于细胞外ATP时，PIP2被消去，K-ATP通道电流降低。