title: Failure of calcium microdomain generation and pathological consequences.
abstract: Normal physiological regulation depends on Ca(2+) microdomains, because there is a need to spatially separate Ca(2+) regulation of different cellular processes. It is only possible to generate local Ca(2+) signals transiently; so, there is an important functional link between Ca(2+) spiking and microdomains. The pancreatic acinar cell provides a useful cell biological model, because of its clear structural and functional polarization. Although local Ca(2+) spiking in the apical (granular) microdomain regulates fluid and enzyme secretion, prolonged global elevations of the cytosolic Ca(2+) 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 Ca(2+) from the endoplasmic reticulum and the fatty acids inhibit markedly mitochondrial ATP generation, which prevents the acinar cell from disposing of the excess Ca(2+) in the cytosol. Because of the abolition of ATP-dependent Ca(2+) pump activity, all intracellular Ca(2+) concentration gradients disappear and the most important part of the normal regulatory machinery is thereby destroyed. The end stage is necrosis.
authors.affiliation: MRC Group, The Physiological Laboratory, University of Liverpool, Crown Street, Liverpool, UK. o.h.petersen@liv.ac.uk
authors.forename: Ole H
authors.initials: OH
authors.lastname: Petersen
authors.forename: Robert
authors.initials: R
authors.lastname: Sutton
authors.forename: David N
authors.initials: DN
authors.lastname: Criddle
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D003600:Cytosol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D004952:Esters / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006706:Homeostasis; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D021962:Membrane Microdomains / Q000502:physiology; D008954:Models, Biological; D010179:Pancreas / Q000166:cytology; D010195:Pancreatitis / Q000503:physiopathology*; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology
chemical_list: D004952:Esters; D005227:Fatty Acids; D053496:Inositol 1,4,5-Trisphosphate Receptors; D019837:Ryanodine Receptor Calcium Release Channel; D000255:Adenosine Triphosphate