Signal transduction, calcium and acute pancreatitis.
Evidence consistently suggests that the earliest changes of acute pancreatitis are intracellular, the hallmark of which is premature intracellular activation of digestive zymogens, accompanied by disruption of normal signal transduction and secretion. Principal components of physiological signal transduction include secretagogue-induced activation of G-protein-linked receptors, followed by generation of inositol 1,4,5-trisphosphate, nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose. In response, calcium is released from endoplasmic reticulum terminals within the apical, granular pole of the cell, where calcium signals are usually contained by perigranular mitochondria, in turn responding by increased metabolism. When all three intracellular messengers are administered together, even at threshold concentrations, dramatic potentiation results in sustained, global, cytosolic calcium elevation. Prolonged, global elevation of cytosolic calcium is also induced by hyperstimulation, bile salts, alcohol and fatty acid ethyl esters, and depends on continued calcium entry into the cell. Such abnormal calcium signals induce intracellular activation of digestive enzymes, and of nuclear factor kappaB, as well as the morphological changes of acute pancreatitis. Depletion of endoplasmic reticulum calcium and mitochondrial membrane potential may contribute to further cell injury. This review outlines current understanding of signal transduction in the pancreas, and its application to the pathophysiology of acute pancreatitis.
Sutton
Robert
R
Department of Surgery, University of Liverpool, 5th Floor UCD Block, Royal Liverpool University Hospital, Daulby Street, Liverpool L69 3GA, UK. r.sutton@liv.ac.uk
Criddle
David
D
Raraty
Michael G T
MG
Tepikin
Alexei
A
Neoptolemos
John P
JP
Petersen
Ole H
OH
D000208:Acute Disease; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D006801:Humans; D010195:Pancreatitis / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology
D002118:Calcium