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Failure of calcium microdomain generation and pathological consequences

Petersen, Ole Holger, Sutton, Robert and Criddle, David N. 2006. Failure of calcium microdomain generation and pathological consequences. Cell Calcium 40 (5-6) , pp. 593-600. 10.1016/j.ceca.2006.08.020

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Normal physiological regulation depends on Ca2+ microdomains, because there is a need to spatially separate Ca2+ regulation of different cellular processes. It is only possible to generate local Ca2+ signals transiently; so, there is an important functional link between Ca2+ spiking and microdomains. The pancreatic acinar cell provides a useful cell biological model, because of its clear structural and functional polarization. Although local Ca2+ spiking in the apical (granular) microdomain regulates fluid and enzyme secretion, prolonged global elevations of the cytosolic Ca2+ concentration are associated with the human disease acute pancreatitis, in which proteases in the granular region become inappropriately activated and digest the pancreas and its surroundings. A major cause of pancreatitis is alcohol abuse and it has now been established that fatty acid ethyl esters and fatty acids, non-oxidative alcohol metabolites, are principally responsible for causing the acinar cell damage. The fatty acid ethyl esters release Ca2+ from the endoplasmic reticulum and the fatty acids inhibit markedly mitochondrial ATP generation, which prevents the acinar cell from disposing of the excess Ca2+ in the cytosol. Because of the abolition of ATP-dependent Ca2+ pump activity, all intracellular Ca2+ concentration gradients disappear and the most important part of the normal regulatory machinery is thereby destroyed. The end stage is necrosis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Systems Immunity Research Institute (SIURI)
Publisher: Elsevier
ISSN: 0143-4160
Last Modified: 04 Jun 2017 06:31

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