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

Research output: Contribution to journalArticlepeer-review

Authors

  • Stephanie L Barrow
  • Svetlana G Voronina
  • Misha A Chvanov
  • Rebecca E Longbottom
  • Oleg V Gerasimenko
  • Ole H Petersen
  • Guy A Rutter
  • Alexei V Tepikin

Colleges, School and Institutes

External organisations

  • University of Liverpool

Abstract

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.

Details

Original languageEnglish
Pages (from-to)1025-39
Number of pages15
JournalPfluegers Archiv: European journal of physiology
Volume455
Issue number6
Publication statusPublished - Mar 2008

Keywords

  • 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