Submembrane ATP and Ca kinetics in a-cells: unexpected signaling for glucagon secretion

Cytoplasmic ATP and Ca are implicated in current models of glucose’s control of glucagon and insulin secretion from pancreatic aand b-cells, respectively, but little is known about ATP and its relation to Ca in a-cells. We therefore expressed the fluorescent ATP biosensor Perceval in mouse pancreatic islets and loaded them with a Ca indicator. With total internal reflection fluorescence microscopy, we recorded subplasma membrane concentrations of Ca and ATP ([Ca]pm; [ATP]pm) in superficial aand b-cells of intact islets and related signaling to glucagon and insulin secretion by immunoassay. Consistent with ATP’s controlling glucagon and insulin secretion during hypoand hyperglycemia, respectively, the dose-response relationship for glucoseinduced [ATP]pm generation was left shifted in a-cells compared to b-cells. Both cell types showed [Ca]pm and [ATP]pmoscillations in opposite phase, probably reflecting energy-consuming Ca transport. Although pulsatile insulin and glucagon release are in opposite phase, [Ca]pm synchronized in the same phase between aand b-cells. This paradox can be explained by the overriding of Ca stimulation by paracrine inhibition, because somatostatin receptor blockade potently stimulated glucagon release with little effect on Ca. The data indicate that an a-cell-intrinsic mechanism controls glucagon in hypoglycemia and that paracrine factors shape pulsatile secretion in hyperglycemia.—Li, J., Yu,Q., Ahooghalandari, P., Gribble, F. M., Reimann, F., Tengholm, A., Gylfe, E. Submembrane ATP and Ca kinetics in a-cells: unexpected signaling for glucagon secretion. FASEB J. 29, 3379–3388 (2015). www.fasebj.org