Failure of calcium microdomain generation and pathological consequences

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.