title: Oscillations of sub-membrane ATP in glucose-stimulated beta cells depend on negative feedback from Ca(2+).
abstract: OBJECTIVE
  ATP links changes in glucose metabolism to electrical activity, Ca(2+) signalling and insulin secretion in pancreatic beta cells. There is evidence that beta cell metabolism oscillates, but little is known about ATP dynamics at the plasma membrane, where regulation of ion channels and exocytosis occur.
  
  
  METHODS
  The sub-plasma-membrane ATP concentration ([ATP]pm) was recorded in beta cells in intact mouse and human islets using total internal reflection microscopy and the fluorescent reporter Perceval.
  
  
  RESULTS
  Glucose dose-dependently increased [ATP]pm with half-maximal and maximal effects at 5.2 and 9 mmol/l, respectively. Additional elevations of glucose to 11 to 20 mmol/l promoted pronounced [ATP]pm oscillations that were synchronised between neighbouring beta cells. [ATP]pm increased further and the oscillations disappeared when voltage-dependent Ca(2+) influx was prevented. In contrast, K(+)-depolarisation induced prompt lowering of [ATP]pm. Simultaneous recordings of [ATP]pm and the sub-plasma-membrane Ca(2+) concentration ([Ca(2+)]pm) during the early glucose-induced response revealed that the initial [ATP]pm elevation preceded, and was temporarily interrupted by the rise of [Ca(2+)]pm. During subsequent glucose-induced oscillations, the increases of [Ca(2+)]pm correlated with lowering of [ATP]pm.
  
  
  CONCLUSIONS
  In beta cells, glucose promotes pronounced oscillations of [ATP]pm, which depend on negative feedback from Ca(2+) . The bidirectional interplay between these messengers in the sub-membrane space generates the metabolic and ionic oscillations that underlie pulsatile insulin secretion.
authors.affiliation: Department of Medical Cell Biology, Biomedical Centre, Uppsala University, Box 571, 75123, Uppsala, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: H Y
authors.initials: HY
authors.lastname: Shuai
authors.forename: E
authors.initials: E
authors.lastname: Gylfe
authors.forename: A
authors.initials: A
authors.lastname: Tengholm
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D000255:Adenosine Triphosphate; D005947:Glucose; D002118:Calcium
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