Submembrane ATP and Ca2+ kinetics in α-cells: unexpected signaling for glucagon secretion.
Cytoplasmic ATP and Ca(2+) 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 Ca(2+) in α-cells. We therefore expressed the fluorescent ATP biosensor Perceval in mouse pancreatic islets and loaded them with a Ca(2+) indicator. With total internal reflection fluorescence microscopy, we recorded subplasma membrane concentrations of Ca(2+) and ATP ([Ca(2+)]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 [Ca(2+)]pm and [ATP]pm oscillations in opposite phase, probably reflecting energy-consuming Ca(2+) transport. Although pulsatile insulin and glucagon release are in opposite phase, [Ca(2+)]pm synchronized in the same phase between α- and β-cells. This paradox can be explained by the overriding of Ca(2+) stimulation by paracrine inhibition, because somatostatin receptor blockade potently stimulated glucagon release with little effect on Ca(2+). The data indicate that an α-cell-intrinsic mechanism controls glucagon in hypoglycemia and that paracrine factors shape pulsatile secretion in hyperglycemia.
*Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom.
Jia
J
Li
*Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom.
Qian
Q
Yu
*Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom.
Parvin
P
Ahooghalandari
*Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom.
Fiona M
FM
Gribble
*Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom.
Frank
F
Reimann
*Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom.
Anders
A
Tengholm
*Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; and Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, United Kingdom erik.gylfe@mcb.uu.se.
Erik
E
Gylfe
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000502:physiology*
D007328:Insulin; D000255:Adenosine Triphosphate; D005934:Glucagon; D005947:Glucose; D002118:Calcium
islet of Langerhans; oscillations; paracrine; signal transduction