Submembrane ATP and Ca2+ kinetics in α-cells: unexpected signaling for glucagon secretion

Cytoplasmic ATP and Ca2+ are implicated in current models of glucose's control of glucagon and insulin secretion from pancreatic α‐and β‐cells, respectively, but little is known about ATP and its relation to Ca2+ in α‐cells. We therefore expressed the fluorescent ATP biosensor Perceval in mouse pancreatic islets and loaded them with a Ca2+ indicator. With total internal reflection fluorescence microscopy, we recorded subplasma membrane concentrations of Ca2+ and ATP ([Ca2+]pm; [ATP]pm)in superficial α‐and β‐cells of intact islets and related signaling to glucagon and insulin secretion by immunoassay. Consistent with ATP's controlling glucagon and insulin secretion during hypo‐ and hyperglycemia, respectively, the dose‐response relationship for glucose‐induced [ATP]pm generation was left shifted in α‐cells compared to β‐cells. Both cell types showed [Ca2+]pm and [ATP]pm oscillations in opposite phase, probably reflecting energy‐consuming Ca2+ transport. Although pulsatile insulin and glucagon release are in opposite phase, [Ca2+]pm synchronized in the same phase between α‐and β‐cells. This paradox can be explained by the overriding of Ca2+ stimulation by paracrine inhibition, because somatostatin receptor blockade potently stimulated glucagon release with little effect on Ca2+. The data indicate that an α‐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 Ca2+ kinetics in α‐cells: unexpected signaling for glucagon secretion. FASEB J. 29, 3379‐3388 (2015). www.fasebj.org