Philipson L H, Rosenberg M P, Kuznetsov A, Lancaster M E, Worley J F, Roe M W, Dukes I D
Department of Medicine, University of Chicago, Illinois 60637.
J Biol Chem. 1994 Nov 11;269(45):27787-90.
Glucose stimulation of pancreatic beta-cell insulin secretion is closely coupled to alterations in ion channel conductances and intracellular Ca2+ ([Ca2+]i). To further examine this relationship after augmentation of voltage-dependent K+ channel expression, transgenic mice were produced which specifically overexpress a human insulinoma-derived, tetraethylammonium (TEA)-insensitive delayed rectifier K+ channel in their pancreatic beta-cells as shown by immunoblot of isolated islets and immunohistochemical analysis of pancreas sections. Whole-cell current recordings confirmed the presence of high amplitude TEA-resistant K+ currents in transgenic islet cells, whose expression correlated with hyperglycemia and hypoinsulinemia. Stable overexpression of the channel in insulinoma cells attenuated glucose-activated increases in [Ca2+]i and prevented the induction of TEA-dependent [Ca2+]i oscillations. These results, employing the first ion channel transgenic mouse, demonstrate the importance of membrane potential regulation in excitation-secretion coupling in the pancreatic beta-cell.
胰腺β细胞胰岛素分泌的葡萄糖刺激与离子通道电导和细胞内Ca2+（[Ca2+]i）的变化密切相关。为了在增强电压依赖性K+通道表达后进一步研究这种关系，制备了转基因小鼠，通过分离胰岛的免疫印迹和胰腺切片的免疫组织化学分析表明，其胰腺β细胞中特异性过表达一种源自人胰岛素瘤的、对四乙铵（TEA）不敏感的延迟整流K+通道。全细胞电流记录证实转基因胰岛细胞中存在高幅度的TEA抗性K+电流，其表达与高血糖和低胰岛素血症相关。该通道在胰岛素瘤细胞中的稳定过表达减弱了葡萄糖激活的[Ca2+]i增加，并阻止了TEA依赖性[Ca2+]i振荡的诱导。这些结果利用第一只离子通道转基因小鼠，证明了膜电位调节在胰腺β细胞兴奋-分泌偶联中的重要性。
