ATP depletion inhibits Ca2+ release, influx and extrusion in pancreatic acinar cells but not pathological Ca2+ responses induced by bile |
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Authors: | 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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Institution: | (1) The Physiological Laboratory, The University of Liverpool, Crown Street, Liverpool, L69 3BX, UK;(2) Department of Cell Biology, Division of Medicine, Imperial College, London, Sir Alexander Fleming Building, Exhibition Road, London, SW7 2AZ, UK;(3) Present address: Centre for Neuroscience, University of California Davis, 1544 Newton Court, Davis, CA 95616, USA |
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Abstract: | Here, we describe novel mechanisms limiting a toxic cytosolic Ca2+ rise during adenosine 5′-triphosphate (ATP) depletion. We studied the effect of ATP depletion on Ca2+ 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 Ca2+ extrusion, which was accompanied by a remarkably synchronous inhibition of store-operated Ca2+ influx. Alternative inhibition of Ca2+ extrusion by carboxyeosin had a much smaller effect on Ca2+ influx. The coordinated metabolic inhibition of Ca2+ influx and extrusion suggests the existence of a common ATP-dependent master regulator of both processes. ATP-depletion also
suppressed acetylcholine (ACh)-induced Ca2+ oscillations, which was due to the inhibition of Ca2+ release from internal stores. This could be particularly important for limiting Ca2+ toxicity during periods of hypoxia. In contrast, metabolic control of Ca2+ influx and Ca2+ release from internal stores spectacularly failed to prevent large toxic Ca2+ 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 Ca2+ release from internal stores nor Ca2+ influx triggered by bile acids were inhibited by ATP depletion, emphasising the danger of these pathological mechanisms.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | Calcium signalling Calcium influx Pancreas ATP Calcium release |
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