title: Calcium and adenosine triphosphate control of cellular pathology: asparaginase-induced pancreatitis elicited via protease-activated receptor 2.
abstract: Exocytotic secretion of digestive enzymes from pancreatic acinar cells is elicited by physiological cytosolic Ca(2+) signals, occurring as repetitive short-lasting spikes largely confined to the secretory granule region, that stimulate mitochondrial adenosine triphosphate (ATP) production. By contrast, sustained global cytosolic Ca(2+) elevations decrease ATP levels and cause necrosis, leading to the disease acute pancreatitis (AP). Toxic Ca(2+) signals can be evoked by products of alcohol and fatty acids as well as bile acids. Here, we have investigated the mechanism by which l-asparaginase evokes AP. Asparaginase is an essential element in the successful treatment of acute lymphoblastic leukaemia, the most common type of cancer affecting children, but AP is a side-effect occurring in about 5-10% of cases. Like other pancreatitis-inducing agents, asparaginase evoked intracellular Ca(2+) release followed by Ca(2+) entry and also substantially reduced Ca(2+) extrusion because of decreased intracellular ATP levels. The toxic Ca(2+) signals caused extensive necrosis. The asparaginase-induced pathology depended on protease-activated receptor 2 and its inhibition prevented the toxic Ca(2+) signals and necrosis. We tested the effects of inhibiting the Ca(2+) release-activated Ca(2+) entry by the Ca(2+) channel inhibitor GSK-7975A. This markedly reduced asparaginase-induced Ca(2+) entry and also protected effectively against the development of necrosis.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'.
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK Department of Pathophysiology, Medical College, Jinan University, Guangzhou 510632, People's Republic of China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Peng
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK.
authors.forename: Julia V
authors.initials: JV
authors.lastname: Gerasimenko
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Tsugorka
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK Bogomoletz Institute of Physiology, Kiev 01024, Ukraine.
authors.forename: Oleksiy
authors.initials: O
authors.lastname: Gryshchenko
authors.affiliation: Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, UK.
authors.forename: Sujith
authors.initials: S
authors.lastname: Samarasinghe
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK Systems Immunity Research Institute, Cardiff University, Cardiff CF14 4XN, Wales, UK petersenoh@cardiff.ac.uk.
authors.forename: Ole H
authors.identifier: 0000-0002-6998-0380
authors.initials: OH
authors.lastname: Petersen
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK gerasimenkoov@cardiff.ac.uk.
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Gerasimenko
mesh_terms: D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001215:Asparaginase / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D051379:Mice; D008810:Mice, Inbred C57BL; D010195:Pancreatitis / Q000139:chemically induced* / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D044464:Receptor, PAR-2; D000255:Adenosine Triphosphate; D001215:Asparaginase; D002118:Calcium
keywords: adenosine triphosphate; asparaginase; calcium; calcium channels; leukaemia; pancreatitis