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

Abstract

The glucagon-releasing pancreatic α-cells are electrically excitable cells but the signal transduction leading to depolarization and secretion is not well understood. To clarify the mechanisms we studied [Ca 2+] i and membrane potential in individual mouse pancreatic α-cells using fluorescent indicators. The physiological secretagogue l-adrenaline increased [Ca 2+] i causing a peak, which was often followed by maintained oscillations or sustained elevation. The early effect was due to mobilization of Ca 2+ from the endoplasmic reticulum (ER) and the late one to activation of store-operated influx of the ion resulting in depolarization and Ca 2+ influx through voltage-dependent L-type channels. Consistent with such mechanisms, the effects of adrenaline on [Ca 2+] i and membrane potential were mimicked by inhibitors of the sarco(endo)plasmic reticulum Ca 2+ ATPase. The α-cells express ATP-regulated K + (K ATP) channels, whose activation by diazoxide leads to hyperpolarization. The resulting inhibition of the voltage-dependent [Ca 2+] i response to adrenaline was reversed when the K ATP channels were inhibited by tolbutamide. However, tolbutamide alone rarely affected [Ca 2+] i, indicating that the K ATP channels are normally closed in mouse α-cells. Glucose, which is the major physiological inhibitor of glucagon secretion, hyperpolarized the α-cells and inhibited the late [Ca 2+] i response to adrenaline. At concentrations as low as 3 mM, glucose had a pronounced stimulatory effect on Ca 2+ sequestration in the ER amplifying the early [Ca 2+] i response to adrenaline. We propose that adrenaline stimulation and glucose inhibition of the α-cell involve modulation of a store-operated current, which controls a depolarizing cascade leading to opening of L-type Ca 2+ channels. Such a control mechanism may be unique among excitable cells.