Inhibition of voltage-gated potassium channels mediates uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic β cells
Inhibition of voltage-gated potassium channels mediates uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic β cells
复制标题
电压门控钾通道的抑制介导大鼠胰腺β细胞中非羧化骨钙素调节的胰岛素分泌
DOI：
10.1016/j.ejphar.2016.02.060
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发表时间：
2016-04-15
影响因子：
5
通讯作者：
Zhang, Yi
中科院分区：
文献类型：
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作者：
Gao, Jingying;Zhong, Xiangqin;Zhang, Yi
胰岛β细胞分泌胰岛素对维持葡萄糖稳态很重要，并受电活动调节。非羧化骨钙素是一种骨源性蛋白，据报道通过增加胰岛素分泌、刺激β细胞增殖和改善胰岛素敏感性来调节葡萄糖代谢。但未羧化骨钙素调节胰岛素分泌的潜在机制尚不清楚。在本研究中，我们研究了大鼠β细胞中未羧化骨钙素调节的胰岛素分泌与电压门控钾（K-v）通道、电压门控钙通道的关系。用放射免疫法测定胰岛素分泌。使用传统的全细胞膜片钳技术记录通道电流和膜动作电位。钙成像系统分析细胞内Ca2+浓度（[Ca2+](i)）。数据显示，在16.7 mmol/l葡萄糖条件下，未羧化骨钙素单独增加胰岛素分泌和[Ca2+](i)，但在K-v通道阻滞剂四乙基氯化铵存在时，对胰岛素分泌和[Ca2+](i)没有这种影响。在膜片钳实验中，未羧化骨钙素延长动作电位持续时间，显著抑制K-v电流，但对电压门控钙通道的特性没有影响。这些结果表明，K-v通道参与了大鼠胰腺β细胞中未羧化骨钙素调节的胰岛素分泌。通过抑制K-v通道，未羧化骨钙素延长动作电位持续时间，增加细胞内Ca2+浓度，最终促进胰岛素分泌。这一发现为骨钙素调节胰岛素分泌的机制提供了新的见解。(C) 2016 Elsevier B.V.版权所有
Insulin secretion from pancreatic beta cells is important to maintain glucose homeostasis and is regulated by electrical activities. Uncarboxylated osteocalcin, a bone-derived protein, has been reported to regulate glucose metabolism by increasing insulin secretion, stimulating beta cell proliferation and improving insulin sensitivity. But the underlying mechanisms of uncarboxylated osteocalcin-modulated insulin secretion remain unclear. In the present study, we investigated the relationship of uncarboxylated osteocalcin-regulated insulin secretion and voltage-gated potassium (K-v) channels, voltage-gated calcium channels in rat beta cells. Insulin secretion was measured by radioimmunoassay. Channel currents and membrane action potentials were recorded using the conventional whole-cell patch-clamp technique. Calcium imaging system was used to analyze intracellular Ca2+ concentration ([Ca2+](i)). The data show that under 16.7 mmol/l glucose conditions uncarboxylated osteocalcin alone increased insulin secretion and [Ca2+](i), but with no such effects on insulin secretion and [Ca2+](i) in the presence of a K-v channel blocker, tetraethylammonium chloride. In the patch-clamp experiments, uncarboxylated osteocalcin lengthened action potential duration and significantly inhibited K-v currents, but had no influence on the characteristics of voltage-gated calcium channels. These results indicate that K-v channels are involved in uncarboxylated osteocalcin-regulated insulin secretion in rat pancreatic beta cells. By inhibiting K-v channels, uncarboxylated osteocalcin prolongs action potential duration, increases intracellular Ca2+ concentration and finally promotes insulin secretion. This finding provides new insight into the mechanisms of osteocalcin-modulated insulin secretion. (C) 2016 Elsevier B.V. All rights reserved.