ATP depletion inhibits Ca2+ release, influx and extrusion in pancreatic acinar cells but not pathological Ca2+ responses induced by bile

Stephanie L Barrow, Svetlana G Voronina, Gabriela da Silva Xavier, Misha A Chvanov, Rebecca E Longbottom, Oleg V Gerasimenko, Ole H Petersen, Guy A Rutter, Alexei V Tepikin

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36 Citations (Scopus)


Here, we describe novel mechanisms limiting a toxic cytosolic Ca(2+) rise during adenosine 5'-triphosphate (ATP) depletion. We studied the effect of ATP depletion on Ca(2+) signalling in mouse pancreatic acinar cells. Measurements of ATP in isolated cells after adenovirus-mediated expression of firefly luciferase revealed that the cytosolic ATP concentration fell from approximately 1 mM to near zero after treatment with oligomycin plus iodoacetate. ATP depletion resulted in the inhibition of Ca(2+) extrusion, which was accompanied by a remarkably synchronous inhibition of store-operated Ca(2+) influx. Alternative inhibition of Ca(2+) extrusion by carboxyeosin had a much smaller effect on Ca(2+) influx. The coordinated metabolic inhibition of Ca(2+) influx and extrusion suggests the existence of a common ATP-dependent master regulator of both processes. ATP-depletion also suppressed acetylcholine (ACh)-induced Ca(2+) oscillations, which was due to the inhibition of Ca(2+) release from internal stores. This could be particularly important for limiting Ca(2+) toxicity during periods of hypoxia. In contrast, metabolic control of Ca(2+) influx and Ca(2+) release from internal stores spectacularly failed to prevent large toxic Ca(2+) responses induced by bile acids-activators of acute pancreatitis (a frequent and often fatal disease of the exocrine pancreas). The bile acids taurolithocholic acid 3-sulphate (TLC-S), taurochenodeoxycholic acid (TCDC) and taurocholic acid (TC) were used in our experiments. Neither Ca(2+) release from internal stores nor Ca(2+) influx triggered by bile acids were inhibited by ATP depletion, emphasising the danger of these pathological mechanisms.

Original languageEnglish
Pages (from-to)1025-39
Number of pages15
JournalPfluegers Archiv: European journal of physiology
Issue number6
Publication statusPublished - Mar 2008


  • Acetylcholine/pharmacology
  • Adenosine Triphosphate/physiology
  • Animals
  • Antimetabolites/pharmacology
  • Bile/physiology
  • Bile Acids and Salts/pharmacology
  • Calcium/metabolism
  • Calcium Signaling/physiology
  • Cell Separation
  • Cytosol/metabolism
  • Data Interpretation, Statistical
  • Deoxyglucose/pharmacology
  • Energy Transfer
  • Enzyme Inhibitors/pharmacology
  • Extracellular Fluid/metabolism
  • Fluorescent Dyes
  • Mice
  • Oligomycins/pharmacology
  • Pancreas/cytology
  • Rotenone/pharmacology
  • Uncoupling Agents/pharmacology


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