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

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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.