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Role of membrane potential -dependent modulation of the intracellular Ca^<2+> stores

细胞内 Ca^2 储存的膜电位依赖性调节的作用

基本信息

批准号：
16590190
负责人：
YAMAZAWA Toshiko
金额：
$ 2.11万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Spontaneous contraction of intestinal smooth muscles is required for bowel movement and its failure results in disorders including irritable bowel syndrome. Rhythmic spontaneous depolarizations in intestinal smooth muscle cells, often referred to as slow waves, are essential for the movement of the gastrointestinal tract. Interstitial cells of Cajal (ICC) lie adjacent to smooth muscle layers and are implicated to be the pacemaker cells generating slow waves, because mutant mice lacking this cell type show gut rhythm disorders. However, the pace making mechanism remains unclear. These results suggest that myenteric ICC may play multiple roles including pace making for physiological bowel movement. Also, glucose-induced insulin secretion from pancreatic beta-cells requires an increase in the intracellular Ca^<2+> concentration [Ca^<2+>]_i. The generally accepted mechanism is that glucose metabolism results in the activation of voltage-dependent Ca^<2+> channels, which allow an influx of Ca^<2+> causing an increases in [Ca^<2+>]_i that in turn triggers exocytosis of insulin. On the other hand, pancreatic beta;-cells express inositol 1,4,5-trisphosphate receptor (IP_3R), which mediates the release of Ca^<2+> from the intracellular Ca^<2+> store. To study the role of IP_3-induced Ca^<2+> release in insulin secretion, we examined the effect of IP_3 5-phosphatase overexpression on glucose-induced Ca^<2+> response in a beta;-cell line, INS-1. Because IP_3 5-phosphatase specifically hydrolyzes IP_3, the overexpression of IP_3 5-phosphatase should inhibit the IP_3-induced Ca^<2+> release. Indeed, glucose-induced Ca^<2+> response was inhibited INS-1 cells expressing IP_3 5-phosphatase. The inhibitory effect was not observed in INS-1 cells expressing a mutant IP_3 5-phosphatase, which lacked the enzyme activity. These results suggest that IP_3 signaling is involved in the glucose-induced Ca^<2+> response in INS-1 cells.

肠平滑肌的自发收缩是肠道运动所必需的，它的失败会导致包括肠易激综合征在内的疾病。肠道平滑肌细胞的节律性自发去极化，通常被称为慢波，对胃肠道的运动是必不可少的。Cajal间质细胞(ICC)位于平滑肌层附近，可能是产生慢波的起搏细胞，因为缺乏这种细胞类型的突变小鼠表现出肠道节律紊乱。然而，步伐的形成机制仍不清楚。这些结果表明，肌间ICC可能发挥多种作用，包括对生理性肠道运动的起搏。此外，葡萄糖诱导的胰岛β细胞胰岛素分泌需要细胞内[Ca^&lt；2+&gt；]_i浓度的增加。普遍接受的机制是，葡萄糖代谢导致电压依赖性钙通道的激活，这允许钙离子内流，导致[Ca^&lt；2+&gt；]_i增加，进而触发胰岛素的排泄。另一方面，胰岛β细胞表达肌醇1，4，5-三磷酸受体(IP_3R)，该受体介导细胞内钙离子的释放。为了研究IP_3诱导的Ca~(2+)释放在胰岛素分泌中的作用，我们研究了IP_3 5-磷酸酶过表达对β细胞系INS-1葡萄糖诱导的Ca~(2+)&gt；反应的影响。由于IP_3 5-磷酸酶是IP_3的特异性水解酶，IP_3 5-磷酸酶的过度表达应能抑制IP_3诱导的钙离子释放。的确，葡萄糖诱导的钙反应抑制了表达IP_3 5-磷酸酶的INS-1细胞。在表达突变的IP_3 5-磷酸酶的INS-1细胞中未观察到该酶的抑制作用。这些结果提示，IP_3信号转导途径参与了葡萄糖诱导的INS-1细胞内钙离子反应。