Düfer M, Haspel D, Krippeit-Drews P, Aguilar-Bryan L, Bryan J, Drews G
Institute of Pharmacy, Department of Pharmacology and Toxicology, University of Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Pflugers Arch. 2009 Apr;457(6):1351-60. doi: 10.1007/s00424-008-0592-4. Epub 2008 Oct 3.
Pancreatic beta-cells of sulfonylurea receptor type 1 knock-out (SUR1(-/-)) mice exhibit an oscillating membrane potential (V (m)) demonstrating that hyper-polarisation occurs despite the lack of K(ATP) channels. We hypothesize that glucose activates the Na(+)/K(+)-ATPase thus increasing a hyper-polarising current. Elevating glucose in SUR1(-/-) beta-cells resulted in a transient fall in V (m) and Ca(2+) independent of sarcoplasmic and endoplasmic reticulum Ca(2+)-activated ATPase (SERCA) activation. This was not affected by K(+) channel blockade but inhibited by ATP depletion and by ouabain. Increasing glucose also reduced Na(+), an effect reversed by ouabain. Exogenously applied insulin decreased Na(+) and hyper-polarised V (m). Inhibiting insulin signalling in SUR1(-/-) beta-cells blunted the glucose-induced decrease of Ca(2+). Tolbutamide (1 mmol/l) disclosed the SERCA-independent effect of glucose on Ca(2+) in wild-type beta-cells. The data show that in SUR1(-/-) beta-cells, glucose activates the Na(+)/K(+)-ATPase presumably by increasing ATP. Insulin can also stimulate the pump and potentiate the effect of glucose. Pathways involving the pump may thus serve as potential drug targets in certain metabolic disorders.
1型磺脲类受体基因敲除（SUR1(-/-)）小鼠的胰腺β细胞表现出振荡膜电位（V (m)），这表明尽管缺乏K(ATP)通道，但仍会发生超极化。我们推测葡萄糖激活Na(+)/K(+)-ATP酶，从而增加超极化电流。在SUR1(-/-)β细胞中提高葡萄糖水平会导致V (m)和Ca(2+)短暂下降，这与肌浆网和内质网Ca(2+)-激活的ATP酶（SERCA）激活无关。这不受K(+)通道阻断的影响，但会被ATP耗竭和哇巴因抑制。增加葡萄糖水平也会降低Na(+)，哇巴因可逆转这种效应。外源性应用胰岛素会降低Na(+)并使V (m)超极化。在SUR1(-/-)β细胞中抑制胰岛素信号传导会减弱葡萄糖诱导的Ca(2+)降低。甲苯磺丁脲（1 mmol/l）揭示了葡萄糖对野生型β细胞中Ca(2+)的SERCA非依赖性作用。数据表明，在SUR1(-/-)β细胞中，葡萄糖可能通过增加ATP来激活Na(+)/K(+)-ATP酶。胰岛素也可以刺激该泵并增强葡萄糖的作用。因此，涉及该泵的途径可能成为某些代谢紊乱的潜在药物靶点。
