A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic alpha-cell.
The glucagon-releasing pancreatic alpha-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 alpha-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 alpha-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 alpha-cells. Glucose, which is the major physiological inhibitor of glucagon secretion, hyperpolarized the alpha-cells and inhibited the late [Ca(2+)](i) response to adrenaline. At concentrations as low as 3mM, 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 alpha-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.
Liu
Yi-Jia
YJ
Department of Medical Cell Biology, Uppsala University Biomedical Centre, Husargatan 3, Box 571, SE-752 37 Uppsala, Sweden.
Vieira
Elaine
E
Gylfe
Erik
E
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D020013:Calcium Signaling; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D004837:Epinephrine / Q000494:pharmacology; D005934:Glucagon / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects*; D051379:Mice; D015221:Potassium Channels / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D015220:Calcium Channels; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D005934:Glucagon; D005947:Glucose; D002118:Calcium; D004837:Epinephrine