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

肠平滑肌的自发收缩是肠运动所必需的，其失败导致包括肠易激综合征在内的疾病。肠平滑肌细胞的节律性自发去极化，通常称为慢波，是胃肠道运动所必需的。Cajal间质细胞（ICC）位于平滑肌层附近，并被认为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，节奏制定机制仍不清楚。这些结果表明，肌间ICC可能发挥多种作用，包括生理性肠运动的起搏。此外，葡萄糖诱导的胰腺β细胞的胰岛素分泌需要细胞内Ca^2+浓度[Ca^2+] i的增加。普遍接受的机制是葡萄糖代谢导致电压依赖性Ca^2+通道的激活，这允许Ca^2+内流，引起[Ca^2 +] i增加，从而触发胰岛素的胞吐作用。另一方面，胰腺β-细胞表达肌醇1，4，5-三磷酸受体（IP_3R），其介导Ca^2+从细胞内Ca^2+库的释放。为了研究IP_3诱导的Ca^<2+>释放在胰岛素分泌中的作用，我们在β细胞系INS-1中检测了IP_3 5-磷酸酶过表达对葡萄糖诱导的Ca^<2+>反应的影响。由于IP_3 5-磷酸酶特异性地水解IP_3，因此过表达IP_3 5-磷酸酶将抑制IP_3诱导的Ca^<2+>释放。葡萄糖诱导的Ca^<2+>反应被表达IP_3 5-磷酸酶的INS-1细胞抑制。在表达缺乏酶活性的突变型IP_3 5-磷酸酶的INS-1细胞中未观察到抑制作用。这些结果表明，IP_3信号通路参与了葡萄糖诱导的INS-1细胞Ca^2+反应。

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.