Arredouani Abdelilah, Guiot Yves, Jonas Jean-Christophe, Liu Lynne H, Nenquin Myriam, Pertusa José A, Rahier Jacques, Rolland Jean-François, Shull Gary E, Stevens Martine, Wuytack Frank, Henquin Jean-Claude, Gilon Patrick
Unité d'Endocrinologie et Métabolisme, University of Louvain Faculty of Medicine, Brussels, Belgium.
Diabetes. 2002 Nov;51(11):3245-53. doi: 10.2337/diabetes.51.11.3245.
Two sarcoendoplasmic reticulum Ca(2+)-ATPases, SERCA3 and SERCA2b, are expressed in pancreatic islets. Immunocytochemistry showed that SERCA3 is restricted to beta-cells in the mouse pancreas. Control and SERCA3-deficient mice were used to evaluate the role of SERCA3 in beta-cell cytosolic-free Ca(2+) concentration (Ca(2+)) regulation, insulin secretion, and glucose homeostasis. Basal Ca(2+) was not increased by SERCA3 ablation. Stimulation with glucose induced a transient drop in basal Ca(2+) that was suppressed by inhibition of all SERCAs with thapsigargin (TG) but unaffected by selective SERCA3 ablation. Ca(2+) mobilization by acetylcholine was normal in SERCA3-deficient beta-cells. In contrast, Ca(2+) oscillations resulting from intermittent glucose-stimulated Ca(2+) influx and Ca(2+) transients induced by pulses of high K(+) were similarly affected by SERCA3 ablation or TG pretreatment of control islets; their amplitude was increased and their slow descending phase suppressed. This suggests that, during the decay of each oscillation, the endoplasmic reticulum releases Ca(2+) that was pumped by SERCA3 during the upstroke phase. SERCA3 ablation increased the insulin response of islets to 15 mmol/l glucose. However, basal and postprandial plasma glucose and insulin concentrations in SERCA3-deficient mice were normal. In conclusion, SERCA2b, but not SERCA3, is involved in basal Ca(2+) regulation in beta-cells. SERCA3 becomes operative when Ca(2+) rises and is required for normal Ca(2+) oscillations in response to glucose. However, a lack of SERCA3 is insufficient in itself to alter glucose homeostasis or impair insulin secretion in mice.
两种肌质网Ca(2+)-ATP酶，即SERCA3和SERCA2b，在胰岛中表达。免疫细胞化学显示，SERCA3局限于小鼠胰腺的β细胞。使用对照小鼠和SERCA3缺陷小鼠来评估SERCA3在β细胞胞质游离Ca(2+)浓度（[Ca(2+)]c）调节、胰岛素分泌和葡萄糖稳态中的作用。SERCA3缺失并未增加基础[Ca(2+)]c。葡萄糖刺激诱导基础[Ca(2+)]c短暂下降，该下降被毒胡萝卜素（TG）抑制所有SERCA所抑制，但不受选择性SERCA3缺失的影响。在SERCA3缺陷的β细胞中，乙酰胆碱引起的Ca(2+)动员正常。相反，间歇性葡萄糖刺激的Ca(2+)内流导致的[Ca(2+)]c振荡以及高K(+)脉冲诱导的[Ca(2+)]c瞬变，在SERCA缺失或对照胰岛TG预处理中受到类似影响；其振幅增加且缓慢下降阶段受到抑制。这表明，在每次振荡的衰减过程中内质网释放Ca(2+)，这些Ca(2+)是在上行阶段由SERCA3泵入的。SERCA3缺失增加了胰岛对15 mmol/l葡萄糖的胰岛素反应。然而，SERCA3缺陷小鼠的基础和餐后血浆葡萄糖及胰岛素浓度正常。总之，SERCA2b而非SERCA3参与β细胞基础[Ca(2+)]c调节。当[Ca(2+)]c升高时SERCA3开始起作用，并且是对葡萄糖产生正常[Ca(2+)]c振荡所必需的。然而，SERCA3的缺乏本身不足以改变小鼠的葡萄糖稳态或损害胰岛素分泌。
