A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell
A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell
复制标题
DOI：
10.1016/j.ceca.2003.10.002
复制
发表时间：
2004-04-01
期刊：
影响因子：
4
通讯作者：
Gylfe, E
中科院分区：
文献类型：
--
作者：
Liu, YJ;Vieira, E;Gylfe, E
释放胰高血糖素的胰腺a细胞是可电兴奋的细胞，但导致去极化和分泌的信号转导尚不清楚。为了阐明机制，我们使用荧光指示剂研究了单个小鼠胰腺α细胞中的[Ca 2 +]（i）和膜电位。生理性促分泌素L-肾上腺素增加[Ca 2 +]，导致峰值，随后通常是持续振荡或持续升高。早期效应是由于从内质网（ER）动员Ca 2+，晚期效应是由于激活钙库操纵的离子内流，导致去极化和Ca 2+通过电压依赖性L型通道内流。与这些机制一致，肾上腺素对[Ca 2 +]（i）和膜电位的影响被肌浆网（内）Ca 2 + ATP酶抑制剂模拟。α细胞表达ATP调节的K+（K-ATP）通道，其被二氮嗪激活导致超极化。当K-ATP通道被甲苯磺丁脲抑制时，对肾上腺素的电压依赖性[Ca ~（2+）]（i）反应的抑制被逆转。然而，甲苯磺丁脲单独很少影响[Ca 2 +]（i），表明K-ATP通道在小鼠α细胞中通常是关闭的。葡萄糖是胰高血糖素分泌的主要生理抑制剂，使α细胞超极化并抑制对肾上腺素的晚期[Ca 2 +]（i）反应。在低至3 mM的浓度下，葡萄糖对ER中的Ca 2+螯合具有显著的刺激作用，从而放大对肾上腺素的早期[Ca 2 +]（i）反应。我们提出，肾上腺素刺激和葡萄糖抑制的α-细胞涉及调制的存储操作的电流，控制去极化级联导致开放的L-型钙通道。这种控制机制在可兴奋细胞中可能是独特的。(C)2003 Elsevier Ltd.保留所有权利。
The glucagon-releasing pancreatic a-cells are electrically excitable cells but the signal transduction leading to depolarization and secretion is not well understood. To clarify the mechanisms we studied [Ca2+](i) and membrane potential in individual mouse pancreatic alpha-cells using fluorescent indicators. The physiological secretagogue L-adrenaline increased [Ca2+], causing a peak, which was often followed by maintained oscillations or sustained elevation. The early effect was due to mobilization of Ca2+ from the endoplasmic reticulum (ER) and the late one to activation of store-operated influx of the ion resulting in depolarization and Ca2+ influx through voltage-dependent L-type channels. Consistent with such mechanisms, the effects of adrenaline on [Ca2+](i) and membrane potential were mimicked by inhibitors of the sarco(endo)plasmic reticulum Ca2+ ATPase. The alpha-cells express ATP-regulated K+ (K-ATP) channels, whose activation by diazoxide leads to hyperpolarization. The resulting inhibition of the voltage-dependent [Ca2+](i) response to adrenaline was reversed when the K-ATP channels were inhibited by tolbutamide. However, tolbutamide alone rarely affected [Ca2+](i), indicating that the K-ATP channels are normally closed in mouse alpha-cells. Glucose, which is the major physiological inhibitor of glucagon secretion, hyperpolarized the alpha-cells and inhibited the late [Ca2+](i) response to adrenaline. At concentrations as low as 3 mM, glucose had a pronounced stimulatory effect on Ca2+ sequestration in the ER amplifying the early [Ca2+](i) response to adrenaline. We propose that adrenaline stimulation and glucose inhibition of the alpha-cell involve modulation of a store-operated current, which controls a depolarizing cascade leading to opening of L-type Ca2+ channels. Such a control mechanism may be unique among excitable cells. (C) 2003 Elsevier Ltd. All rights reserved.