Abstract
Sphingosine-1-phosphate (S1P) receptor is known to show a variety of actions including endothelial permeability regulation. Multiple S1P receptors including S1P-1 are expressed on pancreatic islets, and S1P, a S1P-1 receptor agonist, was shown to potentiate insulin secretion. However, a precise mechanism of the receptor action is not clear at moment. Using Cre-LoxP system, we made mice specifically lacking S1P-1 receptor gene in pancreatic islet B-cells. The blood glucose levels in fasting state are the same in knockout and control mice. After intraperitoneal glucose challenge, knockout mice were significantly less able to normalize blood glucose levels than were the control mice. In the perifusion experiment for isolated islets, glucose stimulation increased insulin secretion in the control islets, whereas it failed in islets from knockout mice. In isolated pancreatic B-cells from both control and knockout mice, glucose stimulation caused depolarization followed by action potential firing. The membrane capacitance measurement revealed that calcium pulse stimulation could not increase the exocytosis of insulin granules. These results indicate that S1P-1 receptors are essential for B-cell insulin secretion in the exocytotic process at least distal to calcium signals. [J Physiol Sci. 2006;56 Suppl:S118]
