A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell

The glucagon-releasing pancreatic a-cells are electrically excitable cells but the signal transduction leading to depolarization and secretion is not well understood. To clarify the mechanisms we studied [Ca2+](i) and membrane potential in individual mouse pancreatic alpha-cells using fluorescent indicators. The physiological secretagogue L-adrenaline increased [Ca2+], causing a peak, which was often followed by maintained oscillations or sustained elevation. The early effect was due to mobilization of Ca2+ from the endoplasmic reticulum (ER) and the late one to activation of store-operated influx of the ion resulting in depolarization and Ca2+ influx through voltage-dependent L-type channels. Consistent with such mechanisms, the effects of adrenaline on [Ca2+](i) and membrane potential were mimicked by inhibitors of the sarco(endo)plasmic reticulum Ca2+ ATPase. The alpha-cells express ATP-regulated K+ (K-ATP) channels, whose activation by diazoxide leads to hyperpolarization. The resulting inhibition of the voltage-dependent [Ca2+](i) response to adrenaline was reversed when the K-ATP channels were inhibited by tolbutamide. However, tolbutamide alone rarely affected [Ca2+](i), indicating that the K-ATP channels are normally closed in mouse alpha-cells. Glucose, which is the major physiological inhibitor of glucagon secretion, hyperpolarized the alpha-cells and inhibited the late [Ca2+](i) response to adrenaline. At concentrations as low as 3 mM, glucose had a pronounced stimulatory effect on Ca2+ sequestration in the ER amplifying the early [Ca2+](i) response to adrenaline. We propose that adrenaline stimulation and glucose inhibition of the alpha-cell involve modulation of a store-operated current, which controls a depolarizing cascade leading to opening of L-type Ca2+ channels. Such a control mechanism may be unique among excitable cells. (C) 2003 Elsevier Ltd. All rights reserved.