Inhibition of glucose-induced electrical activity in rat pancreatic β-cells by DCPIB, a selective inhibitor of volume-sensitive anion currents
Inhibition of glucose-induced electrical activity in rat pancreatic β-cells by DCPIB, a selective inhibitor of volume-sensitive anion currents
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DOI：
10.1016/j.ejphar.2004.02.030
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发表时间：
2004-04-05
影响因子：
5
通讯作者：
Nilius, B
中科院分区：
文献类型：
--
作者：
Best, L;Yates, AP;Nilius, B
我们研究了依他尼酸衍生物4-（2-丁基-6，7-二氯-2-环戊基-茚满-1-酮-5-基）氧代丁酸（DCPIB）对大鼠胰腺β细胞电活动和胰岛素分泌的影响。DCPIB抑制β细胞中的全细胞VSAC电流，抑制外向和内向电流的IC 50值分别为2.2和1.7 μ M。DCPIB还在葡萄糖激活的细胞中在单通道水平上抑制VSAC。在完整细胞中，DCPIB引起β细胞输入电导的净增加，并诱发对甲苯磺丁脲抑制敏感的外向电流，表明K-ATP通道激活。然而，在常规的全细胞条件下没有明显的KATP通道激活，表明药物可能通过间接机制激活完整细胞中的通道，可能涉及营养代谢。DCPIB抑制β细胞中葡萄糖诱导的电活动，在亚刺激葡萄糖浓度下使细胞膜电位超极化，并在葡萄糖浓度升高至刺激水平时防止去极化。DCPIB对电活动的抑制与葡萄糖刺激的胰岛素从完整胰岛释放的显著抑制有关。可以得出结论，DCPIB抑制β细胞中的电和分泌活性，作为VSAC的相互抑制和K-ATP通道活性的激活的组合结果，从而产生β细胞膜电位的显著超极化。(C)2004 Elsevier B. V.保留所有权利。
We have investigated the effects of the ethacrynic acid derivative 4-(2-butyl-6,7-dichloro-2-cyclopentyl-indan-1-on-5-yl) oxobutyric acid (DCPIB), an inhibitor of the volume-sensitive anion channel (VSAC), on electrical activity and insulin secretion in rat pancreatic beta-cells. DCPIB inhibited whole-cell VSAC currents in beta-cells with IC50 values of 2.2 and 1.7 muM for inhibition of outward and inward currents, respectively. DCPIB also inhibited the VSAC at the single channel level in cells activated by glucose. In intact cells, DCPIB caused a net increase in beta-cell input conductance and evoked an outward current that was sensitive to inhibition by tolbutamide, suggesting K-ATP channel activation. However, no KATP channel activation was evident under conventional whole-cell conditions, suggesting that the drug might activate the channel in intact cells via an indirect mechanism, possibly involving nutrient metabolism. DCPIB suppressed glucose-induced electrical activity in beta-cells, hyperpolarised the cell membrane potential at a substimulatory glucose concentration and prevented depolarisation when the glucose concentration was raised to stimulatory levels. The suppression of electrical activity by DCPIB was associated with a marked inhibition of glucose-stimulated insulin release from intact islets. It is concluded that DCPIB inhibits electrical and secretory activity in the beta-cell as a combined result of a reciprocal inhibition of VSAC and activation of K-ATP channel activities, thus producing a marked hyperpolarisation of the beta-cell membrane potential. (C) 2004 Elsevier B.V. All rights reserved.